Bupropion hydrobromide polymorphs

ABSTRACT

Polymorphous and amorphous forms of bupropion hydrobromide are described.

RELATED APPLICATIONS

This application claims priority to EP 08425545.4, filed Aug. 7, 2008,and to EP 08425617.1 filed Sep. 22, 2008.

FIELD OF THE INVENTION

The present invention relates to polymorphs of bupropion hydrobromideand formulations containing polymorphs of bupropion hydrobromide, aswell as their use for the treatment of conditions (e.g. major depressivedisorder, bipolar depression mood disorder, other mood disorder, anxietydisorders, generalized anxiety disorder, panic disorder, post-traumaticstress disorder, nicotine addiction, obesity, attention-deficithyperactivity disorder, restless legs syndrome, sexual dysfunction, andseasonal affective disorders).

BACKGROUND

Bupropion hydrobromide or 3′-chloro-2-t-butylamino-1-propiophenonehydrobromide is a known antidepressant. See.g., U.S. Pat. Nos.7,241,805; 7,569,611; 7,563,992; 7,563,823; and 7,569,610. Itsstructural formula is:

The neurochemical mechanism of the antidepressant effect of bupropion isnot well known. Bupropion affects chemicals within the brain that nervesuse to send messages to each other. These chemical messengers are calledneurotransmitters. The neurotransmitters that are released by nerves aretaken up again by the nerves that release them for reuse (this isreferred to as reuptake). Many skilled artisans believe that depressionis caused by an imbalance among the amounts of neurotransmitters thatare released. Bupropion is a selective catecholamine (dopamine andnorepinephrine) reuptake inhibitor, and works by inhibiting the reuptakeof the neurotransmitters dopamine and norepinephrine, an action whichresults in more dopamine and norepinephrine made available to transmitmessages to other nerves. It has a small effect, if any, on theserotonin reuptake mechanism. Accordingly, bupropion is unique in thatits major effect is on dopamine, an effect which is not shared byselective serotonin re-uptake inhibitors (SSRIs), e.g. paroxetine(PAXIL®), fluoxetine (PROZAC®), sertraline (ZOLOFT®) or the tricyclicantidepressants or TCAs, e.g. amitriptyline (ELAVIL®), imipramine(TOFRANIL®), desipramine (NORPRAMIN®).

Bupropion can also be used to treat other conditions, non-limitingexamples of which include nicotine addition (e.g. smoking cessation),weight gain (e.g. obesity), Parkinson's disease, and seasonal affectivedisorder.

Bupropion hydrochloride is commercially available as an immediaterelease form (WELLBUTRIN®), a sustained release form (WELLBUTRIN® SR andZYBAN®), and an extended release form ((WELLBUTRIN® XL). BothWELLBUTRIN® SR and ZYBAN® are chemically and pharmaceutically identical.WELLBUTRIN®, WELLBUTRIN® SR and WELLBUTRIN® XL are used clinically forthe management of major depressive disorder, bipolar depression mooddisorder, other mood disorder, anxiety disorders, generalized anxietydisorder, panic disorder, post-traumatic stress disorder, and seasonalaffective disorders, and have been approved for use in the treatment ofmajor depressive disorder. ZYBAN® has been approved as an aid topatients wanting to quit smoking. WELLBUTRIN®, the immediate releaseformulation of bupropion, is dosed three times a day, suitably with 6 ormore hours in between doses. For patients requiring more than 300 mgbupropion a day, each dose is prescribed not to exceed 150 mg. Thisrequires administration of the tablets at least 4 times a day with atleast 4 hours in between doses. The immediate release formulationresults in more than a 75% release of the bupropion into the dissolutionmedia in 45 minutes. The sustained release products are dosed twicedaily, and the extended release products are dosed once daily.

Certain advantages exist in using bupropion for the treatment ofdiseases and conditions. For example, bupropion does not inhibitmonoamine oxidase, and does not significantly block the reuptake ofserotonin, unlike other neuronal monoamine reuptake inhibitors.Administration of bupropion can thus avoid or lessen many adverseeffects commonly associated with other antidepressants such as tricyclicagents and monoamine oxidase inhibitors.

It is known that different crystalline forms of one and the same activedrug can display different characteristics of solubility and hencebioavailability, and thus permit more appropriate use of the active drugaccording to whether one requires slow release (in that case using aless-soluble polymorphous form) or quicker availability of the activedrug (using a more-soluble polymorphous form), accordingly providingeasier modulation of the availability of the drug. Accordingly, it isuseful to have different polymorphous forms, with different chemical andphysical properties, at one's disposal.

The development of a stable bupropion formulation would be an advance inthe art.

DESCRIPTION

While bupropion hydrobromide and three polymorphic forms (I, II, and II)have been previously described (see Background above), the inventionhere concerns the discovery of new crystalline forms of bupropionhydrobromide designated as Forms IV, V, VI and VII respectively. Inaddition, certain other embodiments of the present invention relate tothe amorphous form of bupropion hydrobromide.

Certain embodiments of the present invention relate to a bupropioncomposition that comprises a safe and pharmaceutically effective amountof bupropion hydrobromide and/or a polymorph of bupropion hydrobromide;wherein the composition unexpectedly provides for fewer incidences ofseizures and/or less severe seizures associated with the administrationof bupropion than an otherwise similar or identical compositioncontaining an equivalent molar amount of bupropion hydrochloride.

Certain embodiments of the present invention relate to a bupropioncomposition that comprises a safe and pharmaceutically effective amountof bupropion hydrobromide and/or a polymorph of bupropion hydrobromide;wherein said composition is more stable, than an otherwise similar oridentical composition containing an equivalent molar amount of bupropionhydrochloride and/or a polymorph of bupropion hydrobromide. Inparticular, such a bupropion hydrobromide composition is more stablethan an otherwise similar or identical composition containing anequivalent molar amount of bupropion hydrochloride under certain storageconditions, (for example when stored for 3 months or 6 months at 40degrees C. and 75% relative humidity) as evidenced by a reduced amountof at least one moiety (e.g. degradation product) that is characteristicof bupropion degradation and/or a reduced fluctuation or reduction inpotency after being stored under accelerated storage conditions (forexample after storage for 3 months or 6 months), and/or by a reducedfluctuation in the in-vitro dissolution profile in at least onedissolution medium over a 24 hour period.

Certain embodiments of the present invention relate to methods oftreating a condition comprising administering a safe and effectiveamount of bupropion hydrobromide and/or a polymorph of bupropionhydrobromide to a subject in need of bupropion administration.

Certain embodiments of the present invention further contemplate amethod of preparing a medicament for the treatment of a condition whichcan benefit from the administration of bupropion, comprising bringing aneffective amount of bupropion hydrobromide and/or a polymorph ofbupropion hydrobromide into contact with one or more pharmaceuticallyacceptable excipients.

Certain embodiments relate to compositions comprising a compound offormula I (bupropion hydrobromide):

and/or a polymorph of bupropion hydrobromide, and pharmaceuticallyacceptable carriers, excipients and/or diluents; said composition havinggreater stability than a corresponding pharmaceutical compositioncomprising bupropion hydrochloride and pharmaceutically acceptablecarriers, excipients and/or diluents.

In certain embodiments of the present invention, the bupropion salt canbe in the form of its anhydrous, hydrated, and solvated forms, in theform of prodrugs, and in the individually optically active enantiomersof the bupropion salt, such as for example (+)-bupropion and(−)-bupropion. Suitable pharmaceutically acceptable salts of bupropionfor use in the present invention are more stable than bupropionhydrochloride. In certain embodiments the bupropion hydrobromide saltcan also provide for the reduction or avoidance of incidences ofseizures associated with the administration of bupropion. Suitable saltsof bupropion also include for example, pharmaceutically acceptable acidaddition salts. In certain embodiments, the acid addition salt ofbupropion can be indirectly obtained by the separate addition ofbupropion and an acid to the core formulation.

Certain embodiments of the present invention contemplate the use ofbupropion hydrobromide and/or a polymorph of bupropion hydrobromide toprepare a medicament to treat a condition which can benefit fromadministration of bupropion, wherein said medicament has greaterstability than a corresponding medicament comprising bupropionhydrochloride.

As discussed infra and generally known in the art, appropriatedissolution medium and appropriate conditions for assaying thedissolution characteristics of pharmaceutical dosage forms such astablets are well known in the art and are contained in the United StatesPharmacopoeia and its European or Japanese counterparts, and include byway of example dissolution in USP Type 1 apparatus (Rotating BasketMethod) in 900 ml water; 0.1 N HCl; 0.1NHCl+0.1% Cetrimide; USP bufferpH 1.5; Acetate buffer pH 4.5; Phosphate Buffer pH 6.5; or PhosphateBuffer pH 7.4 at 75 RPM at 37 degrees C. +/−0.5 degrees C. Additionally,other examples of appropriate dissolution media include USP-3 media andUSP-3 dissolution conditions e.g SGF pH 1.2; Acetate buffer pH 4.5 andPhosphate Buffer pH 6.8.

Certain embodiments of the present invention contemplate the use ofbupropion hydrobromide and/or a polymorph of bupropion hydrobromide toproduce once-daily administrable tablets or other dosage forms that arebioequivalent to WELLBUTRIN™ or ZYBANT™/WELLBUTRINT™ SR tablets asdefined by FDA criteria when administered once daily to a subject inneed thereof. In particular at least one of the Tmax, Cmax, or AUCprofile of certain embodiments of the present invention is within80-125% of WELLBUTRIN™ and ZYBAN™/WELLBUTRIN™ when administered oncedaily to a subject in need thereof. In certain embodiments theseformulations are also free of any significant food effect.

Certain embodiments of the present invention provide bupropionhydrobromide dosage forms (e.g. tablets) containing at least one coating(e.g. SMARTCOAT™ coating) which is resistant to dose dumping in highalcohol, (e.g., 40% ethanol).

Certain embodiments of the invention include dosage forms that avoid theso-called dose dumping effect, for example in the presence of ethanol,e.g., 5-40% ethanol. This means that the dosage forms do not deliver theactive ingredient significantly more quickly in the presence of, e.g.,ethanol as compared to normal stomach contents. Such dosage forms areresistant to dose dumping.

Certain embodiments of the present invention include both oral andnon-oral bupropion hydrobromide containing medicaments. For example, theinvention embraces compositions suitable for oral, topical, injectable,inhalation and other modes of administration.

Certain embodiments of the present invention include extended releaseformulations, delayed release formulations, and/or enhanced absorptionformulations.

In a more particular implementation of certain embodiments of theinvention, a bupropion medicament composition comprises (i) a core thatincludes bupropion hydrobromide and/or a polymorph of bupropionhydrobromide, a binder and a lubricant; and (ii) a controlled releasecoat substantially surrounding said core; wherein said compositionprovides controlled release of said bupropion hydrobromide. Suchcompositions optionally can comprise one or more additional coatingssurrounding the core and/or the controlled release coat such as amoisture barrier coat, enteric coat or a coating that affects thephysical integrity and/or appearance of the composition. The binder canbe selected from known pharmaceutical binders such as polyvinyl alcohol.The lubricant also can be selected from known pharmaceutical lubricantssuch as glyceryl behenate. The controlled release coat can include awater-insoluble polymer, a water-soluble polymer, and optionally aplasticizer. The water-insoluble polymer can be selected from a range ofwater insoluble polymers useful in extended release pharmaceuticalcompositions such as ethylcellulose. The water-soluble polymer can beselected from a variety of water-soluble polymers useful in extendedrelease pharmaceutical compositions such as polyvinylpyrrolidone. Theplasticizer if present can be selected from a range of knownplasticizers such as mixtures of polyethylene glycol 4000 and dibutylsebacate. Certain embodiments of these compositions include once-dailyadministrable compositions that are bioequivalent to WELLBUTRIN™ orZYBAN™/WELLBUTRIN™ SR tablets when administered once-daily to a subjectin need thereof. These compositions may or may not exhibit a foodeffect. Further, certain embodiments of these compositions can beresistant to dose dumping in the presence of high alcohol concentrations(e.g., 40% by weight of ethanol).

In another particular implementation of certain embodiments of thepresent invention, the bupropion composition comprises (i) a core thatincludes bupropion hydrobromide and/or a polymorph of bupropionhydrobromide, a binder and a lubricant; and (ii) a controlled releasecoat substantially surrounding said core; wherein said controlledrelease coat includes an aqueous dispersion of a neutral ester copolymerwithout any functional groups, a polyglycol having a melting pointgreater than 55° C., and one or more pharmaceutically acceptableexcipients, wherein said coat is coated onto said core and cured at atemperature at least equal to or greater than the melting point of thepolyglycol. The composition provides controlled release of saidbupropion hydrobromide. Optionally, this medicament can comprise one ormore additional coatings surrounding the core and/or controlled releasecoating such as a moisture barrier coat, enteric coat, coat thatprecludes dose dumping in specific media such as alcohol, and/or acoating that affects the physical stability or integrity of themedicament and/or its physical appearance.

In a particular implementation of certain embodiments of the presentinvention, the bupropion composition comprises multiparticulates.

Certain embodiments of the present invention include controlled releasematrix tablet formulations.

Certain embodiments of the present invention include a bupropioncomposition that comprises a second drug. The second drug (e.g. otheranti-depressants, SSRI's, anti-anxiety agents, atypical antipsychoticdrugs, medications that interact with serotonin neurotransmission,medications that interact with norepinephrine neurotransmission,medications that interact with dopamine neurotransmission) can beadministered in combination with the subject bupropion hydrobromidesalt. The second drug can elicit a synergistic benefit on bupropionefficacy as well as non-synergistic drug combinations. Non-limitingexamples of the second drug include citalopram, escitalopram,venlafaxine, quetiapene, buspirone and mixtures thereof.

In accordance with one aspect of certain embodiments of the presentinvention, there is provided a controlled release composition comprising(i) a core comprising an effective amount of a bupropion hydrobromideand/or a polymorph of bupropion hydrobromide, a binder, a lubricant; and(ii) a controlled release coat surrounding said core; and optionally(iii) a moisture barrier surrounding said controlled release coat or thecore; and; wherein the composition exhibits a dissolution profile suchthat after 2 hours from about more than 0% to about 20%, including allvalues and subranges therebetween; preferably from about 2% to about18%, more preferably from about 4% to about 8%, or about 5%, of thebupropion hydrobromide content is released; after 4 hours from about 15%to about 45%, including all values and subranges therebetween;preferably from about 21% to about 37%, more preferably from about 28%to about 34%, or about 32%, of the bupropion hydrobromide content isreleased; after 8 hours from about 40% to about 90%, including allvalues and subranges therebetween, preferably from about 60% to about85%; more preferably from about 68% to about 74%; or about 74%, of thebupropion hydrobromide content is released, and after 16 hours fromabout 80% to about 100% including all values and subranges therebetween,preferably not less than about 93%; more preferably not less than about96%, still more preferably not less than about 99%, of the bupropionhydrobromide content is released, when using a USP apparatus design witha dissolution medium as found in the USP (e.g. USP Apparatus Type 1 at75 rpm, 900 ml, 0.1N HCl, at 37° C.±0.5° C.); and wherein the bupropionhydrobromide composition is more stable than an otherwise similar oridentical composition comprising the equivalent molar amount ofbupropion hydrochloride when each are stored under accelerated storageconditions (e.g. stored for 3 months or 6 months at about 40 degrees C.and at about 75% relative humidity).

In certain embodiments the composition exhibits a dissolution profilesuch that after 2 hours not more than about 0% to about 40%, includingall values and subranges therebetween, of the bupropion hydrobromide isreleased, after 4 hours from about 40% to about 75%, including allvalues and subranges therebetween, of the bupropion hydrobromide isreleased, after 8 hours not less than about 75% to about 99%, includingall values and subranges therebetween, of the bupropion hydrobromide isreleased, and after 16 hours not less than about 85% to about 100%,including all values and subranges therebetween of the bupropionhydrobromide is released, when using a USP apparatus design with adissolution medium as found in the USP (e.g. USP Apparatus Type 1 at 75rpm, 900 ml, 0.1N HCl, at 37° C.±0.5° C.).

Certain embodiments of the present invention include a bupropioncomposition that comprises from about 50 mg to about 1000 mg ofbupropion hydrobromide or a polymorph of bupropion hydrobromide,including 75 mg, 100 mg, 125 mg, 150 mg, 174 mg, 175 mg, 200 mg, 225 mg,250 mg, 275 mg, 300 mg, 325 mg, 348 mg, 350 mg, 375 mg, 400 mg, 425 mg,450 mg, 475 mg, 500 mg, 510 mg, 520 mg, 522 mg, 525 mg, 530 mg, 540 mg,550 mg, 560 mg, 570 mg, 575 mg, 580 mg, 590 mg, 600 mg, 625 mg, 650 mg,675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg,900 mg, 925 mg, 950 mg, 975 mg, and all values and ranges therebetween.For example, certain embodiments include a composition which comprises174 mg, 348 mg or 522 mg of bupropion hydrobromide per unit dose.

In accordance with one aspect of certain embodiments of the presentinvention, there is provided an enhanced-absorption tablet comprising(i) a core comprising an effective amount of bupropion hydrobromideand/or a polymorph of bupropion hydrobromide, a binder, a lubricant; and(ii) a controlled release coat surrounding said core; and wherein theenhanced absorption tablet exhibits a dissolution profile such thatafter 2 hours, from about 0% to about 25%, preferably from about 10% toabout 20%, including all values and subranges therebetween of thebupropion hydrobromide content is released; after 4 hours from about 25%to about 55%, preferably from about 30% to about 50%, including allvalues and subranges therebetween of the bupropion hydrobromide contentis released; after 8 hours from about 60% to about 99%, preferably fromabout 70% to about 90%, including all values and subranges therebetweenof the bupropion hydrobromide content is released, and after 16 hoursfrom about 70% to about 100%, preferably more than about 80%, includingall values and subranges therebetween, of the bupropion hydrobromidecontent is released, when using a USP apparatus design with adissolution medium as found in the USP (e.g. USP Apparatus Type 1 at 75rpm, 900 ml, 0.1N HCl, at 37° C.±0.5° C.); and wherein the bupropionhydrobromide enhanced-absorption tablet is more stable than an otherwisesimilar or identical composition comprising the equivalent molar amountof bupropion hydrochloride when each are stored under acceleratedstorage conditions (e.g. stored for 3 months or 6 months at about 40degrees C. and at about 75% relative humidity.

In certain embodiments the bupropion hydrobromide composition cancomprise a dissolution profile such that after 2 hours from more thanabout 0% to about 40%, including all values and subranges therebetween,of bupropion hydrobromide is released therefrom; after 4 hours fromabout 40% to about 75%, including all values and subranges therebetween,of bupropion hydrobromide is released therefrom; after 8 hours fromabout 75% to about 99%, including all values and subranges therebetween,of bupropion hydrobromide is released therefrom, and after 16 hours fromabout 85% to about 100%, including all values and subrangestherebetween, of bupropion hydrobromide is released therefrom, whenusing a USP apparatus design with a dissolution medium as found in theUSP (e.g. USP Apparatus Type 1 at 75 rpm, 900 ml, 0.1N HCl, at 37°C.±0.5° C.).

As discussed infra, in-vitro dissolution of bupropion from controlled orextended release formulations according to certain embodiments of theinvention can be determined by methods well known to those skilled inthe pharmaceutical art. Suitable methods are contained in the UnitedStates Pharmacopoeia (USP) as well as European and Japanese counterpartsof the USP and are exemplified infra. This includes by way of exampleeffecting dissolution in a USP 1 apparatus (Rotating Type Basket Method)in 900 ml water, 0.1N HCl, 0.1NHCl+0.1% Cetrimide, USP Buffer pH 1.5,Acetate Buffer pH 6.5 or Phosphate Buffer pH 7.4 at 75 RPM at 37 degreesC. +/−0.5 degrees C. or by effecting dissolution using a USP dissolutionmedium such as SGF having a pH 1.2; acetate buffer having a pH of 4.5 orphosphate buffer having a pH of 6.8.

Stable compositions of bupropion hydrobromide (e.g compositions ofbupropion hydrobromide or a polymorph of bupropion hydrobromide withenhanced stability as compared to otherwise similar compositionscontaining bupropion hydrochloride) are known for example from U.S. Pat.No. 7,241,805, U.S. patent application Ser. No. 11/834,848 (Pub. No.2008-0075774), and U.S. patent application Ser. No. 11/930,644 (Pub. No.2008-0274181), the contents of which are incorporated herein byreference.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a flow chart showing the overall process for the developmentof bupropion HBr XL tablets.

FIG. 2 is a flow chart demonstrating the granulation process of thebupropion HBr XL and EA tablets.

FIG. 3 is a flow chart showing the overall tabletting process ofbupropion HBr XL.

FIG. 4 is a flow chart showing the overall coating process of bupropionHBr XL.

FIG. 5 is a dissolution profile of the 4 kp, 6-7 kp and 9-10 kp tablets,comparing the effects of hardness on dissolution in the study on BatchBUP-HBr-XL-009-5.

FIG. 6 is a dissolution profile of the 348 mg Bupropion HBr cores whichhave been compressed using 9 mm tooling in the study on BatchBUP-HBr-XL-009-5.

FIG. 7 is a dissolution profile of the 348 mg Bupropion HBr cores whichhave been compressed using 10 mm tooling in the study on BatchBUP-HBr-XL-009-5.

FIG. 8 is a dissolution profile comparison of the 9 mm and 10 mmdiameter 348 mg Bupropion HBr cores in the study on BatchBUP-HBr-XL-009-5.

FIG. 9 is a dissolution profile of the 174 mg in the study on BatchBUP-HBr-XL-021-5.

FIG. 10 is a dissolution profile of BUP-HBr-XL-348 mg-013-5 (28 mg, 30mg, 32 mg and 34 mg weight gains).

FIG. 11 is a dissolution profile of BUP-HBr-XL-348 mg-013-5 (5 mg, 6 mg,and 7 mg weight gains).

FIG. 12 is a dissolution profile of BUP-HBr-XL-348 mg-018-5 (26 mg, 28mg, 30 mg and 32 mg weight gains).

FIG. 13 is a dissolution profile of BUP-HBr-XL-348 mg-018-5 (7 mg weightgain).

FIG. 14 is a dissolution profile of BUP-HBr-XL-174 mg-022-5 (22 mg, 24mg, 28 mg and 30 mg weight gains).

FIG. 15 is a dissolution profile of BUP-HBr-XL-174 mg-022-5 (5 mg, 6 mg,and 7 mg weight gains).

FIG. 16 is a dissolution profile of BUP-HBr-XL-348 mg-023-5 (26 mg, 28mg, 30 mg and 32 mg weight gains).

FIG. 17 is a dissolution profile of BUP-HBr-XL-348 mg-025-5 (26 mg, 28mg, 30 mg, and 32 mg mg weight gains).

FIG. 18 is a dissolution profile of BUP-HBr-XL-348 mg-025-5 (5 mg, 6 mg,and 7 mg weight gains).

FIG. 19 is a dissolution profile of BUP-HBr-XL-348 mg-026-5 (26 mg, 28mg, 30 mg, and 32 mg weight gains).

FIG. 20 is a dissolution profile of BUP-HBr-XL-174 mg-027-5 (22 mg, 24mg, and 26 mg weight gains).

FIG. 21 is a dissolution profile of BUP-HBr-XL-174 mg-027-5 (4 mg, 5 mg,6 mg, and 7 mg weight gains).

FIG. 22 is a graph showing the relative powder X-ray diffraction (PXRD)for bupropion hydrobromide polymorphic form I.

FIG. 23 is a graph showing the differential scanning calorimetry (DSC)profile of bupropion hydrobromide polymorphic form I.

FIG. 24 is a graph of the relative PXRD of a sample of bupropionhydrobromide polymorphic form I after 6 months under the ICH(International Conference on Harmonisation of Technical Requirements forRegistration of Pharmaceuticals for Human Use) conditions (40.degree.C., 75% R.H.).

FIG. 25 is a graph showing the relative PXRD for bupropion hydrobromidepolymorphic form II.

FIG. 26 is a graph showing the DSC profile of bupropion hydrobromidepolymorphic form II.

FIG. 27 is a graph of the PXRD of a sample of bupropion hydrobromidepolymorphic form II after 1 month under ICH conditions (40.degree. C.,75% R.H.).

FIG. 28 is a graph showing the relative PXRD for bupropion hydrobromidepolymorphic form III.

FIG. 29 is a graph showing the DSC profile of bupropion hydrobromidepolymorphic form III.

FIG. 30 is a graph of the PXRD of a sample of bupropion hydrobromidepolymorphic form III after 1 month under ICH conditions (40.degree. C.,75% R.H.).

FIG. 31 is a graph showing the relative PXRD for bupropion hydrobromidepolymorphic form IV.

FIG. 32 is a graph showing the DSC profile of bupropion hydrobromidepolymorphic form IV.

FIG. 33 is a graph showing the TGA profile of bupropion hydrobromidepolymorphic form IV.

FIG. 34 is a graph showing the IR profile of bupropion hydrobromidepolymorphic form IV.

FIG. 35 is a graph showing the relative PXRD for bupropion hydrobromidepolymorphic form V.

FIG. 36 is a graph showing the DSC profile of bupropion hydrobromidepolymorphic form V.

FIG. 37 is a graph showing the TGA profile of bupropion hydrobromidepolymorphic form V.

FIG. 38 is a graph showing the IR profile of bupropion hydrobromidepolymorphic form V.

FIG. 39 is a graph showing the relative PXRD for bupropion hydrobromidepolymorphic form VI.

FIG. 40 is a graph showing the DSC profile of bupropion hydrobromidepolymorphic form VI.

FIG. 41 is a graph showing the TGA profile of bupropion hydrobromidepolymorphic form VI.

FIG. 42 is a graph showing the IR profile of bupropion hydrobromidepolymorphic form VI.

FIG. 43 is a graph showing the relative PXRD for bupropion hydrobromidepolymorphic form VII.

FIG. 44 is a graph showing the DSC profile of bupropion hydrobromidepolymorphic form VII.

FIG. 45 is a graph showing the TGA profile of bupropion hydrobromidepolymorphic form VII.

FIG. 46 is a graph showing the IR profile of bupropion hydrobromidepolymorphic form VII.

FIG. 47 is a graph showing the relative PXRD for an amorphous form ofbupropion hydrobromide.

FIG. 48 is a graph showing the relative PXRD for an amorphous form ofbupropion hydrobromide.

DEFINITIONS

The following definitions are provided in order to more specificallydescribe the invention. Otherwise all terms are to be accorded theirordinary meaning as they would be construed by one of ordinary skill inthe art, i.e. pharmaceutical drug formulations.

The term “bupropion hydrobromide” as used herein means the bupropionhydrobromide salt, and can also mean the anhydrous, hydrated andsolvated forms, prodrugs, polymorphs, and the individually opticallyactive enantiomers of bupropion hydrobromide.

The terms “adverse effects associated with bupropion” or “side effectsof bupropion” as used herein are used interchangeably, and mean theadverse drug reactions resulting from the administration of bupropion ora mixture of bupropion with one or more other drugs, non-limitingexamples of which include seizures, nausea, vomiting, excitement,agitation, blurred or blurry vision, restlessness, postural tremors,hallucinations/confusional states with the potential for abuse, anxiety,insomnia, headaches and/or migraines, dry mouth, constipation, tremors,sleeping disturbances, dermatologic problems (e.g., rashes),neuropsychiatric signs and symptoms (e.g., delusions and paranoia),weight gain, and combinations thereof.

The term “depression” as used herein refers to any nervous systemdisorder and/or mental condition. Non-limiting examples of “depression”include major depressive disorder, bipolar depressed mood disorder,adjustment mood disorder, and post-partum mood disorder.

The term “condition” as used herein when referring to the administrationof bupropion, means a condition, disease or disorder which can betreated with bupropion. Non-limiting examples of which includedepression, seasonal affective disorder, anxiety disorders, generalizedanxiety disorder, social anxiety disorder, obsessive compulsivedisorder, post traumatic stress disorder (PTSD), panic disorder,disorders requiring a stimulant effect, attention-deficit/hyperactivitydisorder (ADHD), narcolepsy, hypersomnia, substance-abuse disorders,stimulant dependence, marijuana dependence, nicotine dependence,obesity, female and male sexual dysfunction (e.g. prematureejaculation), premenstrual syndrome, premenstrual dysphoric disorder,neuropathic pain, fibromyalgia, diabetic neuropathy, viral infection,sleep apnea, sleep disorders, migraines, Parkinson's disease, restlesslegs syndrome, and combinations thereof.

The terms “treatment”,“treating” or “treat” as used herein whenreferring to a condition, and as understood in the art, are defined tomean an approach for obtaining beneficial or desired results, includingclinical results. “Treatment” can also mean prolonging survival of asubject as compared to the expected survival of the subject if notreceiving treatment.

The term “palliating” as used herein when referring to a condition meansthat the extent and/or undesirable clinical manifestations of acondition or disease state are lessened and/or time course of theprogression is slowed or lengthened, as compared to not treating thecondition.

The term “effective amount” or “pharmaceutically effective amount” asused herein are used interchangeably, and are defined to mean the amountor quantity of the active drug (e.g. bupropion hydrobromide) orpolymorph or enantiomer thereof which is sufficient to elicit anappreciable biological response when administered to a patient. It willbe appreciated that the precise therapeutic dose will depend on the ageand condition of the patient and the nature of the condition to betreated and will be at the ultimate discretion of the attendantphysician.

The terms “enhanced stability”, “greater stability”, “increasedstability” or “more stable” as used herein when referring to bupropionhydrobromide, can be used interchangeably in this application, and aredefined to mean that the bupropion hydrobromide or compositioncontaining bupropion hydrobromide, shows less degradation as determinedby the formation of less of at least one degradation productcharacteristic of bupropion degradation, than an equivalent molar amountof bupropion hydrochloride or an otherwise similar or identicalcomposition containing an equivalent molar amount of bupropionhydrochloride, when exposed to similar or identical conditions.Non-limiting examples of conditions are those described for example inU.S. Pat. No. 7,241,805.

The term “less degradation” as used herein when referring to bupropionhydrobromide or a composition containing bupropion hydrobromide, isdefined to mean any measurable decrease in the amount of at least onebupropion degradation impurity characteristic of bupropion degradation,and/or any measurable difference in the retention of potency, relativeto an equivalent molar amount of bupropion hydrochloride or an otherwisesimilar or identical composition containing an equivalent molar amountof bupropion hydrochloride, when exposed to similar or identicalconditions.

The terms “degradation product”, “bupropion degradation product”,“bupropion degradation impurity” or “impurity” as used herein whenreferring to the degradation of bupropion, are used interchangeably andare defined to include those listed on page 281 of the 26th edition ofthe USP and any other degradation product that may appear as peaks on achromatogram during the assay that are characteristic of bupropiondegradation.

The term “dissolution profile” or “release profile” as used herein areused interchangeably in this application, and are defined to mean aquality control test conducted according to instructions found in theUnited States Pharmacopoeia (“USP”), i.e. using a USP apparatus designwith a dissolution medium as found in the USP. Dissolution testsin-vitro measure the rate and extent of dissolution of the active drugin an aqueous dissolution medium. The dissolution rate or in-vitrorelease rates of drug from the modified release dosage forms of thepresent invention can be measured using one of many USP apparatusdesigns and dissolution media; non-limiting examples of which include aUSP Type 1 apparatus design or USP Type 2 apparatus design, with adissolution medium selected from water; 0.1N HCl; 0.1N HCl with addedSodium Chloride (e.g. 15.7 g NaCl/Litre); 0.1N HCl with added 0.1%Cetrimide; USP Buffer pH 1.5; Acetate Buffer pH 4.5; Phosphate Buffer pH6.5; Phosphate Buffer pH 6.8; and Phosphate Buffer pH 7.4. The terms “%released” and “% dissolved”, when referring to a dissolution profile,are used interchangeably in this application and are defined to mean theextent (%) of active drug released in an aqueous dissolution medium (invitro).

The term “dose dumping” as used herein in respect of “alcohol induceddose dumping” is defined to mean the unintended premature release(in-vitro) of at least one drug from a modified release dosage form. Theterm “premature release” as used herein is defined to mean a release ofat least one drug from a modified release dosage form in 0.1 N HClcontaining alcohol (e.g. dissolution medium containing from about 5% toabout 40% ethanol, the balance being 0.1 N HCl) wherein the rate ofrelease is faster than the rate of release of the identical drug(s) fromthe identical modified release dosage form in the otherwise identical0.1 N HCl not containing alcohol. A non-limiting example of an “alcoholinduced dose dumping” is the premature release of bupropion from amodified release tablet over a period of about 2 hours when dissolutionis tested in 900 ml of Alcohol USP comprising dissolution media usingUSP Apparatus Type 1 at 75 rpm at 37° C. In certain embodiments the term“Alcohol USP comprising dissolution media” means any dissolution mediacomprising from about 5% to about 40% (v/v) of Alcohol USP (e.g. 5%ethanol and 95% 0.1N HCl; 20% ethanol and 80% 0.1N HCl; and 40% ethanoland 60% 0.1N HCl).

The terms “resistant to alcohol”, “resistant to ethanol”, “resistant todose dumping”, “resistant to alcohol-induced dose dumping” and“resisting dose dumping” as used herein are used interchangeably, andare defined to mean the ability of the dosage form to modify release(in-vitro) of the at least one drug while in the presence of alcohol(e.g. from about 5% to about 40% ethanol), such that there is not apremature release of the at least one drug from the modified releasedosage form. For example, in certain embodiments the rate of release ofat least one drug from a modified release dosage form in dissolutionmedia containing alcohol (e.g. dissolution medium containing from about5% to about 40% ethanol) is slower than the rate of release of theidentical drug(s) from the identical modified release dosage form indissolution media not containing alcohol (e.g. dissolution mediumcontaining about 100% 0.1 N HCl).

The term “other drug” or “second drug” as used herein means a drug otherthan bupropion, including but not limited to anti-depression agents,other neuropsychiatric drugs, atypical antipsychotics, drug that affectscentral or peripheral serotonin neurotransmission, drugs that affectcentral norepinephrine neurotransmission, drugs that affect centraldopamine neurotransmission, vasodilators, anti-anxiety agents, appetitemodulators, sleep modulating drugs, SSRIs, anti-viral agents, anti-painagents, anti-migraine agents, anti-inflammatories (both steroidal andnon-steroidal) serotonin receptor agonists, and more particularly caninclude citalopram, escitalopram, venlafaxine, clozapine, melperone,amperozide, iloperidone, risperidone, quetiapene, olanzapine,ziprasidone, aripiprazole, reboxetine, Viagra®, sertraline, paroxetine,fluoxetine, gabapentin, valproic acid, amitriptyline, lofepramine,fluvoxamine, imipramine, mirtazapine, nefazodone, nortriptyline, SAM-E,buspirone, combinations thereof, and their pharmaceutically acceptablesalts (e.g. the hydrochloride salts, the hydrobromide salts, thehydroiodide salts, and the saccharinate salts), as well as theanhydrous, hydrated, and solvated forms, polymorphs, prodrugs, and theindividually optically active enantiomers of the other drug.

The term “dosage form” as used herein is defined to mean apharmaceutical preparation or system in which a dose of at least oneactive drug is included. For example, a dosage form can include at leastone modified release dosage form, at least one osmotic dosage form, atleast one erosion modified release dosage form, at least one dissolutionmodified release dosage form, at least one diffusion modified releasedosage form, at least one modified release matrix core, at least onemodified release matrix core coated with at least one modified releasecoat, at least one enteric coated dosage form, at least one dosage formsurrounded by at least one osmotic subcoat, capsules, minitablets,caplets, uncoated microparticles, microparticles coated with at leastone modified release coat, or any combination thereof.

The term “medicament” as used herein refers to oral and non-oral dosageforms, including but not limited to, all modified release dosage forms,osmosis controlled release systems, erosion controlled release systems,dissolution controlled release systems, diffusion controlled releasesystems, matrix tablets, enteric coated tablets, single and doublecoated tablets (including the extended release and enhanced absorptiontablets as described herein), capsules, minitablets, caplets, coatedbeads, granules, spheroids, pellets, microparticles, suspensions,topicals such as transdermal and transmucosal compositions and deliverysystems (containing or not containing matrices), injectables, andinhalable compositions.

“Modified release dosage forms” as used herein is defined (e.g. as bythe United States Pharmacopoeia “USP”) as those whose drug releasecharacteristics of time course and/or location are chosen to accomplishtherapeutic or convenience objectives not offered by conventionalimmediate release dosage forms. The rate of release of the active drugfrom a modified release dosage form is controlled by features of thedosage form and/or in combination with physiologic or environmentalconditions rather than by physiologic or environmental conditions alone.The modified release dosage forms of certain embodiments can becontrasted with conventional immediate release dosage forms whichtypically produce large maximum/minimum plasma drug concentrations(Cmax/Cmin) due to rapid absorption of the drug into the body (i.e.,in-vivo, relative to the drug's therapeutic index; i.e., the ratio ofthe maximum drug concentration needed to produce and maintain adesirable pharmacological response). In conventional immediate releasedosage forms, the drug content is released into the gastrointestinaltract within a short period of time, and plasma drug levels peak shortlyafter dosing. The design of conventional immediate release dosage formsis generally based on getting the fastest possible rate of drug release,and therefore absorbed, often at the risk of creating undesirable doserelated side effects. The modified release dosage forms of certainembodiments of the invention, on the other hand, improve the therapeuticvalue of the active drug by reducing the ratio of the maximum/minimumplasma drug concentration (Cmax/Cmin) while maintaining drug plasmalevels within the therapeutic window. The modified release dosage formsof certain embodiments attempt to deliver therapeutically effectiveamounts of bupropion hydrobromide and mixtures of bupropion hydrobromidewith at least one other drug as a once-daily dose so that the ratioCmax/Cmin in the plasma at steady state is less than the therapeuticindex, and to maintain drug levels at constant effective levels toprovide a therapeutic benefit over a period of time (e.g. 24-hourperiod). The modified release dosage forms of certain embodiments of theinvention, therefore, avoid large peak-to-trough fluctuations normallyseen with conventional or immediate release dosage forms and can providea substantially flat serum concentration curve throughout thetherapeutic period. Modified-release dosage forms can be designed toprovide a quick increase in the plasma concentration of the bupropionsalt which remains substantially constant within the therapeutic rangeof bupropion salt for a period of time (e.g. 24-hour period).Alternatively, modified-release dosage forms can be designed to providea quick increase in the plasma concentration of the drug, which althoughmay not remain constant, declines at a rate such that the plasmaconcentration remains within the therapeutic range for a period of time(e.g. 24-hour period). The modified release dosage forms of certainembodiments of the invention can be constructed in many forms known toone of ordinary skill in the drug delivery arts and described in theprior art. The USP considers that the terms controlled release,prolonged release and sustained release are interchangeable.Accordingly, the terms “modified-release”, controlled-release”,“control-releasing”, “rate-controlled release”, “extended release”,“prolonged-release”, and “sustained-release” are used interchangeablyherein. For the discussion herein, the definition of the term“modified-release” encompasses the scope of the definitions for theterms “extended release”, “enhanced-absorption”, “controlled release”,“sustained release” and “delayed release”.

“Controlled release dosage forms”, “control-releasing dosage forms”,“rate-controlled release dosage forms”, or dosage forms which exhibit a“controlled release” of the bupropion hydrobromide or mixtures ofbupropion hydrobromide and a second drug, as used herein are usedinterchangeably in this application and are defined to mean dosage formswhich release the bupropion hydrobromide in a controlled manner per unittime in-vivo. For example, controlled release dosage forms can beadministered once daily, and release the bupropion hydrobromide at acontrolled rate and provide plasma concentrations of the drug thatremain controlled with time within the therapeutic range of bupropionover a 24-hour period.

“Sustained-release dosage forms” or dosage forms which exhibit a“sustained-release” of bupropion hydrobromide or mixtures of bupropionhydrobromide and a second drug as used herein is defined to mean dosageforms administered at least once-daily that provide a release ofbupropion hydrobromide sufficient to provide a therapeutic dose soonafter administration, and then a gradual release over a period of timesuch that the sustained-release dosage form provides a therapeuticbenefit over a period of time (e.g. a 12-hour or 24-hour period).

“Extended-release dosage forms” or dosage forms which exhibit an“extended release” of bupropion hydrobromide or mixtures of bupropionhydrobromide and a second drug as used herein is defined to mean dosageforms administered at least once-daily that release the bupropionhydrobromide slowly, so that plasma concentrations of the bupropionhydrobromide are maintained at a therapeutic level for an extendedperiod of time such that the extended release dosage form providestherapeutic benefit over a period of time (e.g. 24-hour period).

“Delayed-release dosage forms” or dosage forms which exhibit a “delayedrelease” of bupropion hydrobromide or mixtures of bupropion hydrobromideand a second drug as used herein is defined to mean dosage formsadministered at least once-daily that do not effectively release drugimmediately following administration but at a later time.Delayed-release dosage forms provide a time delay prior to thecommencement of drug-absorption. This time delay is referred to as “lagtime and should not be confused with “onset time” which representslatency, that is, the time required for the drug to reach minimumeffective concentration.

“Enhanced absorption dosage forms” or dosage forms which exhibit an“enhanced absorption” of the active drug as used herein is defined tomean dosage forms that when exposed to like conditions, will show higherrelease and/or more absorption of the bupropion base as compared toother dosage forms with the same or higher amount of bupropion base. Thesame therapeutic effect can be achieved with less bupropion base in theenhanced absorption dosage form as compared to other dosage forms.

The term “microparticle”, as used herein refers to a drug formulation indiscrete particulate form, and is interchangeable with the terms“microspheres”, “spherical particles”, “microcapsules”, “particles”,“multiparticulates”, “granules”, “spheroids”, beads” and “pellets”.

The term “tablet” as used herein refers to a single dosage form, i.e.the single entity containing the active pharmaceutical agent that isadministered to the subject. The term “tablet” also includes a tabletthat may be the combination of one or more “minitablets”.

The term “controlled release matrix” as used herein is defined to mean adosage form in which the bupropion hydrobromide or mixtures of bupropionhydrobromide and a second drug, is dispersed within a matrix, whichmatrix can be either insoluble, soluble, or a combination thereof.Controlled release matrix dosage forms of the insoluble type are alsoreferred to as “insoluble polymer matrices”, “swellable matrices”, or“lipid matrices” depending on the components that make up the matrix.Controlled release matrix dosage forms of the soluble type are alsoreferred to as “hydrophilic colloid matrices”, “erodible matrices”, or“reservoir systems”. Controlled release matrix dosage forms of theinvention refer to dosage forms comprising an insoluble matrix, asoluble matrix or a combination of insoluble and soluble matrices inwhich the rate of release is slower than that of an uncoated non-matrixconventional or immediate release dosage forms or uncoated “normalrelease matrix” dosage forms. Controlled release matrix dosage forms canbe coated with a “control-releasing coat” to further slow the release ofthe bupropion salt from the controlled release matrix dosage form. Suchcoated controlled release matrix dosage forms can exhibit“modified-release”, controlled-release”, “sustained-release”,“extended-release”, “prolonged-release”, “delayed-release” orcombinations thereof of the active drug.

The term “normal release matrix” as used herein is defined to meandosage forms in which the bupropion hydrobromide or mixtures ofbupropion hydrobromide and a second drug, is dispersed within a matrix,which matrix can be either insoluble, soluble, or combinations thereofbut constructed such that the release of the active drug mimics therelease rate of an uncoated non-matrix conventional or immediate releasedosage form comprising the drug. The release rate from normal releasematrix dosage forms can be slowed down or modified in conjunction with acontrolled release coat.

The terms “osmotic dosage form”, “osmotic delivery device”, “modifiedrelease osmotic dosage form” or “controlled release osmotic dosage form”as used herein are used interchangeably in this application, and aredefined to mean dosage forms which dispense the bupropion hydrobromideor mixture of bupropion hydrobromide and a second drug, all or in partas a result of the presence of an osmotic agent in the dosage formdriving solvent (e.g. water, dissolution media, gastric fluid,intestinal fluid, or mixtures thereof) into the core of the dosage form,which subsequently facilitates the release of drug from the core.

The terms “osmotic agent”, “osmagent”, “osmotically effective solute”,“osmotic enhancer” “osmotically effective compounds”, “osmotic solutes”,“osmopolymer” and “osmotic fluid imbibing agents” as used herein areused interchangeably, and define any material that is soluble (i.e. canbe partially or totally solubilized) or swellable in a solvent (e.g.water) that enters the composition, and which exhibits an osmoticpressure gradient across the selectively-permeable membrane (e.g.controlled release coat), thus increasing the hydrostatic pressureinside the osmotic dosage form.

The terms “controlled release coat”, “control releasing coat”, “modifiedrelease coat” and “rate-controlling coat” as used herein are usedinterchangeably in this application, and are defined to mean afunctional coat which comprises at least one modified release polymer.Non-limiting examples of modified release polymers include pHindependent polymers, pH dependent polymers (such as for example entericor reverse enteric types), soluble polymers, insoluble polymers, lipids,lipidic materials, and mixtures thereof. When applied onto a dosageform, the controlled release coat can modify (e.g. slow) the rate ofrelease of the active drug. For example, the controlled release coat canbe designed such that when the coat is applied onto a dosage form, thedosage form in conjunction with the controlled release coat, exhibits a“modified-release”, “controlled-release”, “sustained-release”,“extended-release” and/or “delayed-release” profile. Combinationsthereof are permissible. The controlled release coat can optionallycomprise additional materials that can alter the functionality of thecontrolled release coat. The term “modified release” is interchangeablewith the terms “controlled release”, “control releasing” and “ratecontrolling”. The term “coat” is interchangeable with the term“coating”.

The terms “moisture barrier” and “moisture barrier coat” as used hereinare used interchangeably and are defined to mean a coating which impedesor retards the absorption of moisture. It is known that bupropion saltsare hygroscopic and, as such, are susceptible to decomposition over timeunder high humidity conditions. Other active drugs can also besusceptible to decomposition over time under high humidity conditions.The proportion of the components of the moisture barrier and the amountof the moisture barrier applied onto the controlled release coat is suchthat the moisture barrier does not fall within the USP definition andrequirement for an enteric coat. Suitably, the moisture barrier iscomprised of an enteric and/or acrylic polymer, suitably an acrylicpolymer, optionally a plasticizer, and a permeation enhancer. Thepermeation enhancer is a hydrophilic substance, which allows water toenter without physical disruption of the coating. The moisture barriercan additionally contain other conventional inert excipients, which canimprove processing of the extended-release formulation described herein.

The term “enteric coat” as used herein is defined to mean a coating orbarrier applied to a dosage form that can control the location in thedigestive system where the active drug(s) is absorbed. For example, anenteric coating can be used to: (i) protect the drug from thedestructive action of the enzymes or low pH environment of the stomach;(ii) prevent nausea or bleeding associated with the irritation of thegastric mucosa by the drug; and/or (iii) deliver the drug in anundiluted form in the intestine. Based on these criteria, in certainembodiments, the enteric coated dosage form can be regarded as a type ofdelayed release dosage form. They differ from sustained release dosageforms in that with sustained release dosage forms, the drug release isextended over a period of time to maintain therapeutic blood levels andto decrease the incidence of side effects caused by a rapid release;whereas, with enteric coatings, the primary objective is to confine therelease of the drug to a predetermined region of the gastrointestinaltract. Enteric coatings work by presenting a surface that issubstantially stable at acidic pH, but breaks down at higher pH to allowrelease of the drug in the intestine.

The term “enteric polymer” as used herein is defined to mean a polymericsubstance that when used in an enteric coat formulation, issubstantially insoluble and/or substantially stable under acidicconditions exhibiting a pH of less than about 5 and which aresubstantially soluble or can decompose under conditions exhibiting a pHof about 5 or more. Non-limiting examples of such enteric polymersinclude carboxymethylethylcellulose, cellulose acetate phthalate,cellulose acetate succinate, methylcellulose phthalate,hydroxymethylethylcellulose phthalate, hydroxypropylmethylcellulosephthalate, hydroxypropylmethylcellulose acetate succinate, polyvinylalcohol phthalate, polyvinyl butyrate phthalate, polyvinyl acetalphthalate, a copolymer of vinyl acetate/maleic anhydride, a copolymer ofvinylbutylether/maleic anhydride, a copolymer of styrene/maleic acidmonoester, a copolymer of methyl acrylate/methacrylic acid, a copolymerof styrene/acrylic acid, a copolymer of methyl acrylate/methacrylicacid/octyl acrylate, a copolymer of methacrylic acid/methyl methacrylateand mixtures thereof. Enteric polymers can be used individually or incombination with other hydrophobic or hydrophilic polymers in an entericcoat, a normal release matrix core, a controlled release matrix core,and/or in a controlled release coat. Enteric polymers can be combinedwith other pharmaceutically acceptable excipients to either facilitateprocessing of a coat comprising the enteric polymer or to alter thefunctionality of the coat.

The term “functional coat” as used herein is defined to mean a coatingthat affects the rate of release in-vitro or in-vivo of the activedrug(s).

The term “non-functional coat” as used herein is defined to mean acoating that does not substantially affect the rate of release in-vitroor in-vivo of the active drug, but can enhance the chemical, biological,physical stability characteristics, or the physical appearance of themodified release dosage form.

The term “core” as used herein is defined to mean a solid vehicle inwhich at least one active drug is uniformly or non-uniformly dispersed.The core can be formed by methods and materials well known in the art,such as for example by compressing, fusing, or extruding the active drugtogether with at least one pharmaceutically acceptable excipient. Thecore can be manufactured into, for example, a homogenous ornon-homogenous unitary core, a multiparticle, or a plurality ofmicroparticles compressed into a unitary core. Non-limiting examples ofcores include microparticle cores, matrix cores, and osmotic cores. Thecore(s) can be coated with at least one functional coat and/ornon-functional coat.

The terms “modified release matrix core”, “controlled release matrixcore” or “matrix core” when referring to a controlled release matrixdosage form, as used herein are used interchangeably, and are defined tomean a core in which at least one active drug is dispersed within amatrix which controls or delays the release of the active drug over a24-hour period so as to allow a composition comprising the modifiedrelease matrix core to be administered as a once-a-day composition. Therelease rate of the active drug from the modified release matrix corecan be modified by the porosity and tortuosity of the matrix, (i.e. itspore structure). The addition of pore-forming hydrophilic salts,solutes, or wicking agents can influence the release rate, as can themanipulation of processing parameters. For example, the compressionforce used in the manufacture of the modified release matrix core canalter the porosity of the matrix core and hence the rate of release ofthe active drug. It will be understood by one of ordinary skill in theart of drug delivery that a more rigid matrix will be less porous andhence release the active drug more slowly compared to a less rigidmodified release matrix core. The modified release matrix core cancomprise insoluble or inert matrix dosage forms, swellable matrix dosageforms, swellable and erodable matrix dosage form, hydrophobic matrixdosage forms, hydrophilic matrix dosage forms, erodable matrix dosageforms, reservoir dosage forms, or any combination thereof. The modifiedrelease matrix core can comprise at least one insoluble matrix, at leastone swellable matrix, at least one swellable and erodable matrix, atleast one hydrophobic matrix, at least one hydrophilic matrix, at leastone erodable matrix, or a combination thereof in which the rate ofrelease is slower than that of uncoated immediate-release dosage forms.Modified release matrix cores can be coated with at least one controlledrelease coat to further slow the release of the active drug from themodified release matrix core. Such coated modified release matrix corescan exhibit modified-release, controlled-release, sustained-release,extended-release, prolonged-release, bi-phasic release, delayed-releaseor combinations thereof of the active drug. Modified release matrixcores can also be coated with a non-functional soluble coat.

The term “plasticizer” as used herein includes any compounds capable ofplasticizing or softening a polymer or a binder used in the presentinvention. The use of plasticizers is optional, and can be included inthe dosage form to modify the properties and characteristics of thepolymers used in the coat(s) or core of the dosage form for convenientprocessing during manufacture of the coat(s) and/or the core of thedosage form. Once the coat(s) and/or core have been manufactured,certain plasticizers can function to increase the hydrophilicity of thecoat(s) and/or the core of the dosage form in the environment of use.During manufacture of the coat(s) and/or core, the plasticizer can lowerthe melting temperature or glass transition temperature (softening pointtemperature) of the polymer or binder. Plasticizers can be included witha polymer and lower its glass transition temperature or softening point.Plasticizers also can reduce the viscosity of a polymer. Plasticizerscan impart some particularly advantageous physical properties to thedosage forms of the invention.

The terms “pore former”, “pore forming agent”, and “pore formingadditive” as used herein are used interchangeably in this application,and are defined to mean an excipient that can be added to a coating(e.g. the controlled release coat), wherein upon exposure to fluids inthe environment of use, the pore former dissolves or leaches from thecoating to form pores, channels or paths in the coating, that can fillwith the environmental fluid and allow the fluid to enter the core anddissolve the active drug, and modify the release characteristics of theformulation. The pore formers can be inorganic or organic, and includematerials that can be dissolved, extracted or leached from the coatingin the environment of use.

The term “steady state” as used herein means that the blood plasmaconcentration curve for a given drug does not substantially fluctuateafter repeated doses to dose of the formulation.

“AUC” as used herein means area under the plasma concentration-timecurve, as calculated by the trapezoidal rule over a time interval (e.g.complete 24-hour interval); and signifies the extent of the absorptionof a drug.

“Cmax” as used herein means the highest plasma concentration of the drugattained within the dosing interval (e.g., 24 hours).

“Cmin” as used herein means the minimum plasma concentration of the drugattained within the dosing interval (e.g. 24 hours).

“Cavg” as used herein means the plasma concentration of the drug withinthe dosing interval (e.g. 24-hours), and is calculated as AUC/dosinginterval.

“Tmax” as used herein means the time period which elapses afteradministration of the dosage form at which the plasma concentration ofthe drug attains the highest plasma concentration of drug attainedwithin the dosing interval (e.g. 24 hours).

The term “bioequivalence” as used herein is defined as there being abouta 90% or greater probability that the bioavailability (AUC) of theactive drug as determined by standard methods is from about 80% to about125% of the second orally administrable dosage form comprising the samedose of the active drug and that there is about 90% or greaterprobability that the maximum blood plasma concentration (Cmax) of theactive drug as measured by standard methods is from about 80% to about125% of the second orally administrable dosage form. For example, thereader is referred to the final version of the guidance approved by theUS Food and Drug Administration at the time of filing of this patentapplication i.e., the March 2003 Guidance for Industry Bioavailabilityand Bioequivalence Studies for Orally Administered Drug Products GeneralConsiderations, U.S. Department of Health and Human Services, Food andDrug Administration, Center for Drug Evaluation and Research (CDER), fora detailed discussion on bioequivalence.

The terms “a”, “an” or “at least one” as used herein are usedinterchangeably in this application, and are defined to mean “one” or“one or more”.

The numerical parameters set forth in the following specification andattached claims that are modified by the term “about”, areapproximations that can vary depending upon the technological propertiesof the particular case. For example, the term “about” can mean within anacceptable error range (e.g. standard deviations) for the particularvalue as determined by one of ordinary skill in the art, which willdepend in part on how the value is measured or determined, e.g., thelimitations of the measurement system.

Other terms are defined as they appear in the following description andshould be construed in the context with which they appear.

The present invention encompasses the bupropion hydrobromide salt andpolymorphs of bupropion hydrobromide, and compositions containing safeand pharmaceutically effective levels of the bupropion hydrobromide saltand/or polymorph of bupropion hydrobromide, that can be used for thetreatment of a condition in subjects that can benefit from bupropionadministration, wherein the bupropion hydrobromide salt and compositionscontaining safe and pharmaceutically effective levels of the bupropionhydrobromide salt unexpectedly provide for the reduction of incidencesof and/or the reduction in severity of bupropion-induced seizures, andare more stable, as compared with equivalent molar amounts of bupropionhydrochloride or otherwise similar or identical compositions containingequivalent molar amounts of bupropion hydrochloride. Results aredescribed for example in U.S. Pat. No. 7,241,805, and U.S. patentapplication Ser. No. 11/834,848 (Pub. No. 2008-0075774), the contents ofwhich are incorporated herein by reference.

Also, the present invention encompasses polymorphs thereof and specificpurified enantiomeric forms thereof. The present invention alsoencompasses the use of such bupropion hydrobromide salt and compositionscontaining the bupropion hydrobromide salt for the treatment of one ormore conditions in a subject suitable for treatment by bupropion orpharmaceutically acceptable salts thereof (e.g. depression, obesity,nicotine addiction, and other conditions treatable with bupropion suchas are disclosed herein); wherein the incidences of and/or the severityof bupropion-induced seizures is reduced as compared with an equivalentmolar amount of bupropion hydrochloride or an otherwise similar oridentical composition containing an equivalent molar amount of bupropionhydrochloride.

The present invention encompasses any medicament containing apharmaceutically effective amount of bupropion hydrobromide and/or apolymorph of bupropion hydrobromide. This includes both oral andnon-orally administrable medicaments such as topicals, injectables,aerosols and other inhalable medicaments. Particularly such medicamentcompositions include orally administrable modified release dosage formscontaining bupropion hydrobromide. The dosages can be convenientlypresented in unit dosage form and prepared by any of the methodswell-known in the art of pharmacy. A “solid dosage form” as used herein,means a dosage form that is neither liquid nor gaseous. Dosage formsinclude solid dosage forms, such as tablets, powders, microparticles,capsules, suppositories, sachets, troches, patches and lozenges as wellas liquid suspensions and elixirs. Capsule dosages contain the solidcomposition within a capsule that can be made of gelatin or otherconventional encapsulating material.

The modified release dosage forms contemplated in the present inventioncan be multiparticulate or monolithic. For example, those skilled in thepharmaceutical art and the design of medicaments are aware of modifiedrelease matrices conventionally used in oral pharmaceutical compositionsadopted for modified release and means for their preparation.

A modified release formulation containing bupropion hydrobromide and/ora polymorph of bupropion hydrobromide according to the present inventioncan be coated with one or more functional or non-functional coatings.Non-limiting examples of functional coatings include controlled releasepolymeric coatings, moisture barrier coatings, enteric polymericcoatings, and the like. In at least one embodiment of the presentinvention a bupropion hydrobromide composition comprises a controlledrelease polymeric coating that includes an acrylic polymer. Suitableacrylic polymers include but are not limited to acrylic acid andmethacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethylmethacrylates, cynaoethyl methacrylate, aminoalkyl methacrylatecopolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acidalkylamine copolymer, poly(methyl methacrylate), poly(methacrylic acid)(anhydride), polyacrylamide, poly(methacrylic acid anhydride), glycidylmethacrylate copolymers and mixtures thereof.

In at least one embodiment polymerizable quaternary ammonium compoundsare employed in the controlled release coat, of which non-limitingexamples include quaternized aminoalkyl esters and aminoalkyl amides ofacrylic acid and methacrylic acid, for exampleβ-methacryl-oxyethyl-trimethyl-ammoniummethosulfate,β-acryloxy-propyl-trimethyl-ammonium chloride,trimethylaminomethyl-methacrylamide methosulfate and mixtures thereof.The quaternary ammonium atom can also be part of a heterocycle, as inmethacryloxyethylmethyl-morpholiniom chloride or the correspondingpiperidinium salt, or it can be joined to an acrylic acid group or amethacrylic acid group by way of a group containing hetero atoms, suchas a polyglycol ether group. Further suitable polymerizable quaternaryammonium compounds include quaternized vinyl-substituted nitrogenheterocycles such as methyl-vinyl pyridinium salts, vinyl esters ofquaternized amino carboxylic acids, styryltrialkyl ammonium salts, andmixtures thereof. Other polymerizable quaternary ammonium compoundsuseful in the present invention include acryl- andmethacryl-oxyethyltrimethyl-ammonium chloride and methosulfate,benzyldimethylammoniumethyl-methacrylate chloride,diethylmethylammoniumethyl-acrylate and -methacrylate methosulfate,N-trimethylammoniumpropylmethacrylamide chloride,N-trimethylammonium-2,2-dimethylpropyl-1-methacrylate chloride andmixtures thereof.

In at least one embodiment the acrylic polymer of the controlled releasecoat is comprised of one or more ammonio methacrylate copolymers.Ammonio methacrylate copolymers (e.g. EUDRAGIT® RS and RL) are describedin National Formulary (NF) XVII as fully polymerized copolymers ofacrylic and methacrylic acid esters with a low content of quaternaryammonium groups. Two or more ammonio methacrylate copolymers havingdiffering physical properties can be incorporated in the controlledrelease coat of certain embodiments. For example, it is known that bychanging the molar ratio of the quaternary ammonium groups to theneutral (meth)acrylic esters, the permeability properties of theresultant coating can be modified.

In certain other embodiments of the present invention, the controlledrelease coat further includes a polymer whose permeability is pHdependent, such as anionic polymers synthesized from methacrylic acidand methacrylic acid methyl ester (e.g. EUDRAGIT® L and EUDRAGIT® S).The ratio of free carboxyl groups to the esters is known to be 1:1 inEUDRAGIT® L and 1:2 in EUDRAGIT® S. EUDRAGIT® L is insoluble in acidsand pure water, but becomes increasingly permeable above pH 5.0.EUDRAGIT® S is similar, except that it becomes increasingly permeableabove pH 7. The hydrophobic acrylic polymer coatings can also include apolymer which is cationic in character based on dimethylaminoethylmethacrylate and neutral methacrylic acid esters (e.g. EUDRAGIT® E). Thehydrophobic acrylic polymer coatings of certain embodiments of thepresent invention can further include a neutral copolymer based on poly(meth)acrylates, such as EUDRAGIT® NE. EUDRAGIT® NE 30D lacquer filmsare insoluble in water and digestive fluids, but permeable andswellable.

In at least one other embodiment of the invention, the controlledrelease coat comprises a dispersion of poly (ethylacrylate, methylmethacrylate) 2:1 (KOLLICOAT® EMM 30 D).

In at least one other embodiment of the invention, the controlledrelease coat comprises a polyvinyl acetate stabilized withpolyvinylpyrrolidone and sodium lauryl sulfate such as KOLLICOAT® SR30D.The dissolution profile can be altered by changing the relative amountsof different acrylic resin lacquers included in the coating. Also, bychanging the molar ratio of polymerizable permeability-enhancing agent(e.g., the quaternary ammonium compounds) to the neutral (meth)acrylicesters, the permeability properties (and thus the dissolution profile)of the resultant coating can be modified.

In at least one embodiment of the invention the controlled release coatcomprises ethylcellulose, which can be used as a dry polymer (e.g.ETHOCEL®) solubilised in organic solvent prior to use, or as an aqueousdispersion. One suitable commercially-available aqueous dispersion ofethylcellulose is AQUACOAT®. AQUACOAT® can be prepared by dissolving theethylcellulose in a water-immiscible organic solvent and thenemulsifying the same in water in the presence of a surfactant and astabilizer. After homogenization to generate submicron droplets, theorganic solvent can be evaporated under vacuum to form a pseudolatex.The plasticizer is not incorporated in the pseudolatex during themanufacturing phase. Thus, prior to using the same as a coating, theAQUACOAT® can be intimately mixed with a suitable plasticizer prior touse. Another suitable aqueous dispersion of ethylcellulose iscommercially available as SURELEASE®. This product can be prepared byincorporating plasticizer into the dispersion during the manufacturingprocess. A hot melt of a polymer, plasticizer (e.g. dibutyl sebacate),and stabilizer (e.g. oleic acid) can be prepared as a homogeneousmixture, which can then be diluted with an alkaline solution to obtainan aqueous dispersion which can be applied directly onto substrates.

Other examples of polymers that can be used in the controlled releasecoat include cellulose acetate phthalate, cellulose acetate trimaletate,hydroxy propyl methylcellulose phthalate, polyvinyl acetate phthalate,polyvinyl alcohol phthalate, shellac; hydrogels and gel-formingmaterials, such as carboxyvinyl polymers, sodium alginate, sodiumcarmellose, calcium carmellose, sodium carboxymethyl starch, poly vinylalcohol, hydroxyethyl cellulose, methyl cellulose, ethyl cellulose,gelatin, starch, and cellulose based cross-linked polymers in which thedegree of crosslinking is low so as to facilitate adsorption of waterand expansion of the polymer matrix, hydroxypropyl cellulose,hydroxypropyl methylcellulose, polyvinylpyrrolidone, crosslinked starch,microcrystalline cellulose, chitin, pullulan, collagen, casein, agar,gum arabic, sodium carboxymethyl cellulose, (swellable hydrophilicpolymers) poly(hydroxyalkyl methacrylate) (molecular weight from about5k to about 5000k), polyvinylpyrrolidone (molecular weight from about10k to about 360k), anionic and cationic hydrogels, zein, polyamides,polyvinyl alcohol having a low acetate residual, a swellable mixture ofagar and carboxymethyl cellulose, copolymers of maleic anhydride andstyrene, ethylene, propylene or isobutylene, pectin (molecular weightfrom about 30k to about 300k), polysaccharides such as agar, acacia,karaya, tragacanth, algins and guar, polyacrylamides, POLYOX®polyethylene oxides (molecular weight from about 100k to about 5000k),AQUAKEEP® acrylate polymers, diesters of polyglucan, crosslinkedpolyvinyl alcohol and poly N-vinyl-2-pyrrolidone, hydrophilic polymerssuch as polysaccharides, methyl cellulose, sodium or calciumcarboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropylcellulose, hydroxyethyl cellulose, nitro cellulose, carboxymethylcellulose, cellulose ethers, methyl ethyl cellulose, ethylhydroxyethylcellulose, cellulose acetate, cellulose butyrate, cellulosepropionate, gelatin, starch, maltodextrin, pullulan, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerol fatty acidesters, polyacrylamide, polyacrylic acid, natural gums, lecithins,pectin, alginates, ammonia alginate, sodium, calcium, potassiumalginates, propylene glycol alginate, agar, and gums such as arabic,karaya, locust bean, tragacanth, carrageens, guar, xanthan, scleroglucanand mixtures thereof.

In at least one embodiment the dosage forms are coated with polymers inorder to facilitate mucoadhsion within the gastrointestinal tract.Non-limiting examples of polymers that can be used for mucoadhesioninclude carboxymethylcellulose, polyacrylic acid, CARBOPOL™,POLYCARBOPHIL™, gelatin, other natural or synthetic polymers, andmixtures thereof.

In at least one embodiment of the invention, the dosage form is anextended release tablet comprising: (i) a core that includes bupropionhydrobromide or a polymorph of bupropion hydrobromide in an amount offrom about 40% to about 99% by weight of tablet dry weight, includingall values and ranges therebetween, a binder such as polyvinyl alcoholin an amount of from about 0.5% to about 25% by weight of tablet dryweight, including all values and ranges therebetween, and a lubricantsuch as glyceryl behenate in an amount of from about 0.1% to about 5% byweight of tablet dry weight, including all values and rangestherebetween; and (ii) a controlled release coat that includes awater-insoluble water-permeable film-forming polymer such asethylcellulose in an amount of from about 1% to about 12% by weight oftablet dry weight, including all values and ranges therebetween, awater-soluble polymer such as polyvinylpyrrolidone (POVIDONE® USP) in anamount of from about 1.5% to about 10% by weight of tablet dry weight,including all values and ranges therebetween, optionally a plasticizersuch as dibutyl sebacate, polyethylene glycol 4000 or a mixture thereof,in an amount of from about 0.5% to about 4% by weight of tablet dryweight, including all values and ranges therebetween, and optionally awax such as carnauba wax in an amount of from about 0.01% to about 0.05%by weight of tablet dry weight, including all values and rangestherebetween.

In at least one embodiment of the invention, the dosage form is a 174 mgextended release tablet comprising: (i) a core that includes bupropionhydrobromide or a polymorph of bupropion hydrobromide (e.g. about 81% byweight of tablet dry weight), a binder such as polyvinyl alcohol (e.g.about 3% by weight of tablet dry weight), and a lubricant such asglyceryl behenate (e.g. about 3% by weight of tablet dry weight); and(ii) a controlled release coat that includes a water-insolublewater-permeable film-forming polymer such as ethylcellulose (e.g. about7% by weight of tablet dry weight), a water-soluble polymer such aspolyvinylpyrrolidone (POVIDONE® USP), (e.g. about 4% by weight of tabletdry weight), optionally a plasticizer such as dibutyl sebacate,polyethylene glycol 4000 or a mixture thereof (e.g. about 2% by weightof tablet dry weight), and optionally a wax such as carnauba wax (e.g.about 0.03% by weight of tablet dry weight).

In at least one embodiment of the invention, the dosage form is a 348 mgextended release tablet comprising: (i) a core that includes bupropionhydrobromide or a polymorph of bupropion hydrobromide (e.g. about 87% byweight of tablet dry weight), a binder such as polyvinyl alcohol (e.g.about 3% by weight of tablet dry weight), and a lubricant such asglyceryl behenate (e.g. about 3% by weight of tablet dry weight); and(ii) a controlled release coat that includes a water-insolublewater-permeable film-forming polymer such as ethylcellulose (e.g. about4% by weight of tablet dry weight), a water-soluble polymer such aspolyvinylpyrrolidone (POVIDONE® USP), (e.g. about 2% by weight of tabletdry weight), optionally a plasticizer such as dibutyl sebacate,polyethylene glycol 4000 or a mixture thereof (e.g. about 1% by weightof tablet dry weight), and optionally a wax such as carnauba wax (e.g.about 0.01% by weight of tablet dry weight).

In at least one embodiment of the invention, the dosage form is a 522 mgXL tablet comprising: (i) a core that includes bupropion hydrobromide ora polymorph of bupropion hydrobromide (e.g. about 85% by weight oftablet dry weight), a binder such as polyvinyl alcohol (e.g. about 3.5%by weight of tablet dry weight), and a lubricant such as glycerylbehenate (e.g. about 3.5% by weight of tablet dry weight); and (ii) acontrolled release coat that includes a water-insoluble water-permeablefilm-forming polymer such as ethylcellulose (e.g. about 3% by weight oftablet dry weight), a water-soluble polymer such as polyvinylpyrrolidone(POVIDONE® USP), (e.g. about 3.5% by weight of tablet dry weight),optionally a plasticizer such as dibutyl sebacate, polyethylene glycol4000 or a mixture thereof (e.g. about 1.5% by weight of tablet dryweight), and optionally a wax such as carnauba wax (e.g. about 0.01% byweight of tablet dry weight).

In at least one embodiment a modified release pharmaceutical compositionreleases bupropion hydrobromide or a polymorph of bupropion hydrobromidein a first dissolution medium consisting of 0.1 N HCl and 5%-40% v/vethanol at a rate that is less than or equal to about 1.1 times the rateof release of bupropion hydrobromide or a polymorph of bupropionhydrobromide from an identical modified release pharmaceuticalcomposition in a second dissolution medium consisting of 0.1 N HClmeasured over the time period of at least from 0 to 2 hours. In certainembodiments the term “less than or equal to about 1.1” includes valuesbelow 1.1, such as 1.05, 1.00, 0.95, 0.90, 0.85, 0.80, etc, includingall values and subranges between about 1.1 and about 0, but preferablydoes not equal 0, and more preferably is 0.5-1.1, more preferably0.75-1.1, even more preferably 0.8-1.0. These measurements arepreferably made using a USP Apparatus I at 75 rpm and at 37±0.5° C. Incertain embodiments the modified release pharmaceutical composition isplaced in 900 ml of dissolution medium for the measurement. In otherembodiments the value of “about 1.1” includes values immediately above1.1, such as 1.30, 1.29, 1.28, 1.27, 1.26, 1.25, 1.24, 1.23, 1.22, 1.21,1.20, 1.19, 1.18, 1.17, 1.16, 1.15, 1.14, 1.13, 1.12, 1.11, etc,including all values and subranges therebetween. The results is aredescribed in greater detail in U.S. patent application Ser. No.11/930,644 (Pub. No. 2008-0274181), the contents of which areincorporated herein by reference.

In addition to the modified release dosage forms described herein, othermodified release technologies known to those skilled in the art can beused in order to achieve the modified release formulations of certainembodiments of the present invention. Such formulations can bemanufactured as a modified release oral formulation, for example, in asuitable tablet or multiparticulate formulation known to those skilledin the art. In either case, the modified release dosage form canoptionally include a controlled release carrier which is incorporatedinto a matrix along with the drug, or which is applied as a controlledrelease coating.

Polymorphic Forms I, II and III

It is well known that organic molecules can crystallize into solidforms. Moreover the same organic compound may assume differentcrystalline arrangements in solid form, depending on the conditionsunder which the crystal product is formed. This phenomenon is commonlyknown as polymorphism. A number of studies were undertaken to explorethe polymorphic forms of bupropion hydrobromide. The crystal forms ofthe products obtained in the studies were determined by powder X-raydiffraction (PXRD). A RIGAKU miniflex instrument (Radiation Cu Koc,generator 30 KV, filter Ni) was used to obtain the PXRD data.

A standard procedure was established to generate bupropion hydrobromide,this standard procedure produces a first polymorphic form which has beentermed polymorphic form I. The relative PXRD for Form I is shown in FIG.22. The differential scanning calorimetry (DSC) profile for Form I isshown in FIG. 23. This procedure was scaled up and generated threeindustrial batches. The material obtained from the three industrialbatches consistently gave the same PXRD profile of crystalline form I.Samples of these batches of form I were tested for accelerated stabilityat 3 and 6 months under ICH conditions (40° C., 75% R.H.). All the threebatches gave exactly the same PXRD after 3 and 6 months of stabilitytesting. The PXRD profile of one of the three batches of form I after 6months stability testing is shown in FIG. 24. The complete survey of thestability data is reported in Table 39.

Bupropion hydrobromide of form I has been used as the starting materialin experiments to identify other polymorphic forms. Two additionalpolymorphic forms were identified and have been named form II and formIII. FIGS. 25 and 26 show the PXRD data and DSC profile respectively ofpolymorphic form II. FIG. 27 shows the PXRD profile of form II after 1month stability testing in ICH conditions (40° C., 75% R.H.). FIGS. 28and 29 show the PXRD data and DSC profile respectively of form III. FIG.30 shows the PXRD profile of form III after 1 month stability testing inICH conditions (40° C., 75% R.H.).

Polymorphic form II was obtained by recrystallization of form I fromsolvents or mixtures of solvents such as acetone-water, methanol,dichloromethane, toluene-methanol and dimethylcarbonate-methanol.Polymorphic form III was obtained by recrystallization of polymorphicform I in methanol. Table 39 provides a list of recrystallizationconditions and the polymorphic form obtained under each set ofconditions.

Samples of the polymorphic forms II and III were tested after 1 monthunder the same accelerated stability conditions (ICH conditions of 40°C., 75% R.H.). Polymorphic form II showed no change in the PXRD profileat that time while the PXRD profile of form III showed conversion toform II. This data suggests that polymorphic forms I and II are quitestable while polymorphic form III is not as stable as forms I and IIunder the test conditions. See Example 3 below.

Polymorphic Forms IV, V, VI and VII, and Amorphous Form

During additional experiments of crystallization of bupropionhydrobromide it was found, unexpectedly, that even though numerousexperiments had been conducted previously with the aim of identifyingnew crystalline forms of bupropion hydrobromide (i.e. forms I, II andIII , see Table 39), bupropion hydrobromide can be obtained inadditional polymorphous forms not previously known (i.e. forms IV, V, VIand VII).

Moreover, surprisingly, bupropion hydrobromide was isolated in amorphousform in an experiment with lyophilization of an aqueous solution ofbupropion hydrobromide and in an experiment with evaporation of asolution of the product in p-xylene. These last two results areparticularly unexpected, since test 122 in table 39 (for forms I, II andIII) describes how, by treating aqueous solutions of bupropionhydrobromide by the “spray drying” technique, which usually givesproducts in amorphous form, we obtain instead a product in crystallineform I.

The polymorphous form designated as form IV is characterized by the PXRDprofile shown in FIG. 31, by the DSC profile shown in FIG. 32, by theTGA profile shown in FIG. 33 and by the IR profile shown in FIG. 34.

The polymorphous form designated as form V is characterized by the PXRDprofile shown in FIG. 35, by the DSC profile shown in FIG. 36, by theTGA profile shown in FIG. 37 and by the IR profile shown in FIG. 38.

The polymorphous form designated as form VI is characterized by the PXRDprofile shown in FIG. 39, by the DSC profile shown in FIG. 40, by theTGA profile shown in FIG. 41 and by the IR profile shown in FIG. 42.

The polymorphous form designated as form VII is characterized by thePXRD profile shown in FIG. 43, by the DSC profile shown in FIG. 44, bythe TGA profile shown in FIG. 45 and by the IR profile shown in FIG. 46.

The amorphous form is characterized by the PXRD profile shown in FIG. 47and by the PXRD profile shown in FIG. 48.

The PXRD diffraction patterns were obtained on X-ray powder diffractionPANalytical X'pert Pro equipped with XVelerator, in a measurement rangebetween 3 and 40 2theta. All the DSC experiments were performed with aDSC 7 Perkin Elmer instrument in a temperature range between 25° C. and250° C. with a heating rate of 10° C./min.

All the TGA experiments were conducted with a TGA 7 Perkin Elmerinstrument in a temperature range between 39° C. and 310° C. with aheating rate of 10° C./min.

All the IR spectra were recorded on FT-IR Nicolet from ThermoFischer.

In total, the polymorph screening has identified seven crystalline formsand an amorphous form for Bupropion Hydrobromide. Form II is thethermodynamically stable crystal form as shown by slurry experiments.Form I is a metastable form produced by different experiments butconverts into Form II by slurry for 1 week at both room and hightemperature. Form I and Form II are the cyrstalline forms obtained inthe majority of experiments. Form VII is also found to be a stable formafter 28 days storage. Form IV is only produced by evaporation of achloroform solution of bupropion hydrobromide. Form V is only producedby interaction of bupropion hydrobromide with dioxane. Form VI is onlyproduced by interaction of bupropion hydrobromide with n-propanol andethyl acetate. Form VII is only produced by interaction of bupropionhydrobromide with benzonitrile, methyl benzoate, and tetrahydrofuran.Form I, Form II, Form V, Form VI, Form VII and the amorphous form areanhydrous forms. Form III is a solvate of ethanol. Form IV is a solvatedcrystal form.

Tablets

In certain embodiments of the present invention, there is provided amodified-release tablet having a core comprising bupropion hydrobromideor a polymorph of bupropion hydrobromide and conventional excipients. Incertain embodiments the bupropion hydrobromide salt or the polymorph ofbupropion hydrobromide or the composition comprising the bupropionhydrobromide or polymorph provides for the reduction of incidences ofand/or severity of bupropion-induced seizures, and is more stable ascompared with equivalent molar amounts of bupropion hydrochloride orotherwise similar or identical compositions containing equivalent molaramounts of bupropion hydrochloride. The core can be surrounded by acontrolled release coat which can control the release of bupropionhydrobromide or mixture of bupropion hydrobromide with a second drug. Inother embodiments, a moisture barrier can optionally be added tosurround the controlled release coat. This moisture barrier is optionalgiven the enhanced stability of bupropion hydrobromide relative tobupropion hydrochloride and by selection of an appropriate controlledrelease coating. If present, this moisture barrier can affect in-vitrodrug release as well as precluding moisture from coming into contactwith the bupropion hydrobromide salt. Optionally, this tablet canfurther comprise one or more additional functional or non-functionalcoatings surrounding the core, moisture barrier and/or controlledrelease coat.

Extended Release (XL) Tablets

In certain embodiments of the present invention, there is provided anextended-release (XL) tablet having a core comprising bupropionhydrobromide and/or a polymorph of bupropion hydrobromide andconventional excipients. In certain embodiments the bupropionhydrobromide salt and/or polymorph of bupropion hydrobromide providesfor the reduction of incidences of and/or severity of bupropion-inducedseizures, and is more stable, as compared with equivalent molar amountsof bupropion hydrochloride. The core can be surrounded by a controlledrelease coat, which controls the release of the bupropion hydrobromidesalt or polymorph of bupropion hydrobromide. The tablet optionally cancomprise one or more additional functional or non-functional coatssurrounding the core or controlled release coat. The extended-releasetablet of certain embodiments has unexpected enhanced stability.

The XL Core

The core of the extended-release tablet comprises an effective amount ofthe bupropion hydrobromide salt and/or a polymorph of bupropionhydrobromide, a binder, and a lubricant; and can contain otherconventional inert excipients. The amount of the bupropion hydrobromidesalt or polymorph of bupropion hydrobromide present in the XL core canvary in an amount from about 40% to about 99% by weight of the tabletdry weight, including all values and ranges therebetween. For example,in certain embodiments bupropion hydrobromide and/or a polymorph ofbupropion hydrobromide is present in an amount from about 70% to about95% by weight of the tablet dry weight, including all values and rangestherebetween. For example, in certain embodiments, the core comprisesbupropion hydrobromide and/or a polymorph of bupropion hydrobromide in aproportion of about 40%, about 45%, about 50%, about 55%, about 60%,about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about95% or about 99% of the core dry weight.

In at least one embodiment of a 174 mg dose tablet, the bupropionhydrobromide is present in an amount of from about 75% to about 85% byweight of the tablet dry weight, including all values and rangestherebetween. In at least one embodiment of a 348 mg dose tablet, theamount of bupropion hydrobromide can be present in an amount of fromabout 80% to about 90% by weight of the tablet dry weight, including allvalues and ranges therebetween. In at least one embodiment of a 522 mgdose tablet, the bupropion hydrobromide is present in an amount of fromabout 75% to about 90% by weight of the tablet dry weight, including allvalues and ranges therebetween. In certain embodiments of the 174 mg,348 mg and 522 mg dose bupropion hydrobromide extended-release tabletsof the invention, the amount of bupropion hydrobromide is present in anamount of from about 85% to about 99% by weight of the dry core for eachdose, including all values and ranges therebetween.

A binder (also sometimes called adhesive) can be added to a drug-fillermixture to increase the mechanical strength of the granules and tabletsduring formation. Binders can be added to the formulation in differentways: (1) as a dry powder, which is mixed with other ingredients beforewet agglomeration, (2) as a solution, which is used as agglomerationliquid during wet agglomeration, and is referred to as a solutionbinder, and (3) as a dry powder, which is mixed with the otheringredients before compaction. In this form the binder is referred to asa dry binder. Solution binders are a common way of incorporating abinder into granules. In certain embodiments, the binder used in the XLtablets is in the form of a solution binder. Non-limiting examples ofbinders useful for the core include hydrogenated vegetable oil, castoroil, paraffin, higher aliphatic alcohols, higher aliphatic acids, longchain fatty acids, fatty acid esters, wax-like materials such as fattyalcohols, fatty acid esters, fatty acid glycerides, hydrogenated fats,hydrocarbons, normal waxes, stearic acid, stearyl alcohol, hydrophobicand hydrophilic polymers having hydrocarbon backbones, and mixturesthereof. Specific examples of water-soluble polymer binders includemodified starch, gelatin, polyvinylpyrrolidone, cellulose derivatives(such as for example hydroxypropyl methylcellulose (HPMC) andhydroxypropyl cellulose (HPC)), polyvinyl alcohol and mixtures thereof.The amount of binder present can vary from about 0.5% to about 25% byweight of the tablet dry weight, including all values and rangestherebetween. For example, in certain embodiments the binder is presentin an amount of from about 0.5% to about 15% by weight of the tablet dryweight, including all values and ranges therebetween For example, incertain embodiments of the 174 mg, 348 mg and 522 mg dose tablets, thebinder is present in an amount of from about 1% to about 6% by weight ofeach dry core weight, including all values and ranges therebetween; andin other embodiments at about 3% by weight of each dry core weight. Inat least one embodiment of the 522 mg dose tablet, the binder is presentin an amount of about 4% by weight of dry core weight. In at least oneembodiment of the invention the binder is polyvinyl alcohol.

Lubricants can be added to pharmaceutical formulations to decrease anyfriction that occurs between the solid and the die wall during tabletmanufacturing. High friction during tabletting can cause a series ofproblems, including inadequate tablet quality (capping or evenfragmentation of tablets during ejection, and vertical scratches ontablet edges) and may even stop production. Accordingly, lubricants areadded to tablet formulations of certain embodiments of the XL tabletformulation described herein. Non-limiting examples of lubricants usefulfor the core include glyceryl behenate, stearic acid, hydrogenatedvegetable oils (such as hydrogenated cottonseed oil (STERPTEX®),hydrogenated soybean oil (STEROTEX® HM) and hydrogenated soybean oil &castor wax (STERPTEX® K), stearyl alcohol, leucine, polyethylene glycol(MW 1450, suitably 4000, and higher), magnesium stearate, glycerylmonostearate, stearic acid, polyethylene glycol, ethylene oxide polymers(e.g. CARBOWAX®), sodium lauryl sulfate, magnesium lauryl sulfate,sodium oleate, sodium stearyl fumarate, DL-leucine, colloidal silica,mixtures thereof and others as known in the art. In at least oneembodiment of the present invention, the lubricant is glyceryl behenate(e.g. COMPRITOL® 888). The amount of lubricant present can vary fromabout 0.1% to about 6% by weight of the tablet dry weight, including allvalues and ranges therebetween. For example, in certain embodiments theamount of lubricant present is from about 2% to about 3% by weight ofthe tablet dry weight, including all values and ranges therebetween; andin other embodiments the amount of lubricant present is at about 3% byweight of the tablet dry weight. In certain embodiments of the 174 mg,348 mg and 522 mg dose XL tablets of the invention, the lubricant ispresent in an amount of about 3% by weight of the tablet dry weight, orfrom about 1% to about 6% by weight of the dry core weight, includingall values and ranges therebetween. For example, in certain embodimentsthe lubricant is present in an amount of about 3% by weight of the drycore weight for the 174 mg, 348 mg and 522 mg dose XL tablets. In atleast one embodiment of the 522 mg dose tablet, the lubricant is presentin an amount of about 4% by weight of dry core weight.

At this stage, the XL core formulation of certain embodiments of thepresent invention is an uncoated immediate release formulation resultingin about 100% dissolution of the bupropion hydrobromide salt or apolymorph of bupropion hydrobromide within about 1 hour. In at least oneembodiment the XL core is a normal release matrix formulation. Incertain embodiments the core comprises an effective pharmaceuticalamount of bupropion hydrobromide and/or a polymorph of bupropionhydrobromide, a binder (e.g. polyvinyl alcohol), and a lubricant (e.g.glyceryl behenate). Additional inert excipients consistent with theobjects of the invention can also be added to the core formulation. Theadditional inert excipients can be added to facilitate the preparationand/or improve patient acceptability of the final extended-releasedosage form as described herein. The additional inert excipients arewell known to the skilled artisan and can be found in the relevantliterature, for example in the Handbook of Pharmaceutical Excipients.Non-limiting examples of such excipients include spray dried lactose,sorbitol, mannitol, and any cellulose derivative.

In certain embodiments the core of the bupropion hydrobromidecomposition (e.g. core of an XL tablet) can be made according to any oneof the methods described in U.S. Pat. No. 7,241,805, U.S. patentapplication Ser. No. 11/834,848 (Pub. No. 2008-0075774), or U.S. patentapplication Ser. No. 11/930,644 (Pub. No. 2008-0274181).

In at least one embodiment of the invention, the granules to becompressed to form the core of the bupropion hydrobromide XL tablet ofthe invention described herein, are manufactured by the wet granulationprocess. Wet granulation involves agitation of a powder (the activedrug) by convention in the presence of a liquid (the solution binder)followed by drying. For forming the granules, which are to be eventuallycompressed into the tablet cores, the bupropion hydrobromide salt isfirst granulated, for example, with a solution binder, in a granulator,for example using a fluidized bed granulator (e.g. a fluidized bedgranulator manufactured by Glatt (Germany) or Aeromatic (Switzerland)).The binder (e.g. polyvinyl alcohol) is first dissolved or dispersed in asuitable solvent (e.g. water). The solution binder is then top sprayedonto the drug in a granulator (e.g. a fluidized bed granulator).Alternatively, granulation can also be performed in a conventional orhigh shear mixer. If necessary, the additional inert excipients (e.g. afiller) can be mixed with the bupropion hydrobromide salt prior to thegranulation step.

The granules formed are subsequently dried and then sieved prior toblending the granules with the lubricant. In certain embodiments, thedried granules are sieved through a 1.4 mm mesh screen. The sievedgranules are then blended with the lubricant, and if necessary, anyother additional inert excipients, which can improve processing of theextended-release tablets of the invention. Blending of the granules withthe lubricant, and if necessary, any additional inert excipients, suchas for example a glidant, can be performed in a V-blender or any othersuitable blending apparatus. Glidants can improve the flowability of thepowder. This for example, can be helpful during tablet production athigh production speeds and during direct compaction. However, becausethe requirement for adequate flow is high, a glidant is often also addedto a granulation before tabletting. The blended granules aresubsequently pressed into tablets and are hereinafter referred to astablet cores. Tablet cores can be obtained by the use of standardtechniques and equipment well known to the skilled artisan. For example,the XL tablet cores can be obtained by a rotary press (also referred toas a multi-station press) fitted with suitable punches.

The granules can also be manufactured by using other processes known tothe skilled artisan. Examples of other granule manufacturing processesinclude dry granulation (e.g. slugging, roller compaction), directcompression, extrusion, spheronization, melt granulation, and rotarygranulation.

An example of the granulation process for the XL cores (60 kg batch) isas follows: A Fluid Bed Processor is used for granulation in order toagglomerate the particles of the materials to obtain a uniform particlesize for the final blend. The granulating solution is prepared bydissolving the binder (e.g. polyvinyl alcohol) in hot purified waterwhile mixing. The percent solids content can be adjusted to obtain aviscosity to control the build up (agglomeration size) of the material.A lower viscosity leads to smaller particles, and a higher viscosityleads to larger particles. In addition, the application rate (e.g. fromabout 150 gm/min to about 250 gm/min, including all values and rangestherebetween; or about 200 gm/min), position of Spray gun (e.g. centerposition) and nozzle size (e.g. from about 0.5 mm to about 2 mm,including all values and ranges therebetween; or about 1 mm) andatomization pressure (e.g. from 20 psi to about 40 psi, including allvalues and ranges therebetween; or about 30 psi) contribute further tocontrol particle size. The active material is fluidized and heated (e.g.from about 35° C. to about 45° C., including all values and rangestherebetween; or about 40° C.) prior to start of solution application.During the spray cycle, the bed temperature (e.g. from about 35° C. toabout 45° C.; including all values and ranges therebetween, or about 40°C.) is kept at a constant temperature to avoid over-wetting. Once allthe required binder solution is applied, the material is further driedto the targeted LOD value (i.e. loss on drying) (e.g. below about 1%)prior to unloading. The amount of binder (e.g. polyvinyl alcohol) isfrom about 2% to about 6%, including all values and ranges therebetween,e.g. about 3%; and the solution concentration is from about 3% to about7%, including all values and ranges therebetween, e.g. about 4.5%. Thetime of agglomeration process for the 60 kg batch is from about 45minutes to about 220 minutes including all values and rangestherebetween e.g. about 150 minutes. Once the granulate is dry, materialis passed through a 1.4 and 2.00 mm screen to remove any oversizedparticles. The oversized particles are passed through the mill to reduceoversize particles. Oversized particles are generally not present in anamount to exceed about 5% of total yield. The screened and milledmaterials are placed into a shell blender (e.g. V-Blender, Bin blender)and the lubricant (e.g. glyceryl behenate) is added. The lubricant isscreened and added to the granules and blended at the predeterminednumber of revolutions or time (e.g. mix time of about 5 min to about 15min, including all values and ranges therebetween; e.g. including about10 min). The percent lubricant is from about 0.5% to about 4%, includingall values and ranges therebetween (e.g. including about 2%). The levelof lubrication is established for sufficient coverage of either largeror smaller particle size distribution. Additional characteristicsinclude bulk density (e.g. from about 0.3 gm/ml to about 0.8 gm/ml,including all values and ranges therebetween, e.g. including about 0.5gm/ml), and moisture content (e.g. not more than about 1%). Particlesize and flow of final blend are factors in obtaining uniform fill ofcavities on a rotary press. The flow and top rotation speed of the pressare adjusted (dependant on the type/size of press) so as to notjeopardize the weight uniformity of individual tablets. The productblend is passed through a hopper into a feed frame to fill the diecavities passing under the feed frame. Weight adjustments are made tokeep the weight within the specified range, and adjustments made to thepressure settings to obtain the required hardness. Some componentsmonitored for the tablets are tablet thickness and friability (e.g. lessthan about 0.5%). Suitable thickness (related to overall surface area)and lower friability help reduce core damage and loss of active duringcoating. Tablet samples are removed at predetermined intervals tomonitor specifications.

Coatings

The tablet cores can be coated for administration to a subject. In atleast one embodiment of the invention, the tablet cores are coated witha controlled release coating (“XL Controlled Release Coat”) that canprovide an extended release of the bupropion hydrobromide salt ormixture of the bupropion hydrobromide salt and other drug. In at leastone other embodiment, the tablet cores are coated with an aqueouscontrolled release coating that comprises an aqueous dispersion of aneutral ester copolymer without any functional groups (“AQ ControlledRelease Coat”).

In certain embodiments the tablet dosage form comprises an optionalmoisture barrier in addition to the controlled release coat. Thecontrolled release coat and the moisture barrier can be applied in twostages. The controlled release coat can be applied directly onto thesurface of the tablet cores and functions to control the release of thebupropion hydrobromide salt. The moisture barrier can be applieddirectly onto the surface of the controlled release coat to impede orretard the absorption of moisture.

Prophetic examples of controlled release coat formulations are providedbelow. It should be understood that the constituents and/or proportionsof the constituents in these coatings as well as the amounts thereof canbe varied in order to achieve formulations possessing different releasecharacteristics. In all instances wherein prophetic examples areprovided these compositions are intended to be exemplary and it shouldbe understood that the specific procedures, constituents, amountsthereof and the like can be varied in order to obtain a compositionpossessing desired properties.

In at least one embodiment the controlled release coat is a coatingformulation that provides a delayed release of the active drug(s) fromthe tablet core. In such embodiments the coating formulation to beapplied to the core can comprise:

EUDRAGIT ® L12.5 about 50% by weight of coating suspension Triethylcitrate about 0.63% by weight of coating suspension Talc about 1.25% byweight of coating suspension Isopropyl alcohol about 48.12% by weight ofcoating suspension Solids total = about 8.1% Polymer content of about6.3% suspension =

In certain embodiments the controlled release coating of the bupropionhydrobromide dosage form (e.g. controlled release coat of an XL tablet)can be made according to any one of the methods described herein.

Preparation of the controlled release coating formulation of suchembodiments (e.g. controlled release coat that can provide a delayedrelease of the active drug) can be as follows: Talc and triethyl citrateare homogenized in the solvent by means of a homogenizer forapproximately 10 minutes. The suspension is poured directly into theEUDRAGIT® L12.5 dispersion and stirred gently to avoid sedimentation.The coating is sprayed onto tablets until approximately 5 mg/cm2 ofEUDRAGIT® L has been applied to the tablet core.

In at least one embodiment the controlled release coat can provide asustained release of the active drug from the tablet core. The coatingformulation can comprise:

EUDRAGIT ® RL 12.5 about 10% by weight of coating suspension EUDRAGIT ®RS 12.5 about 30% by weight of coating suspension Dibutyl sebacate about0.5% by weight of coating suspension Talc about 3.5 g by weight ofcoating suspension Magnesium stearate about 1% by weight of coatingsuspension Acetone about 27.5% by weight of coating suspension Isopropylalcohol about 27.5% by weight of coating suspension Solids total = about10% Polymer content of about 5% suspension =

Preparation of the controlled release coating formulation of suchembodiments (i.e. controlled release coat that can provide a sustainedrelease of the active drug) can be as follows: Dibutyl sebacate, talcand magnesium stearate are mixed and finely dispersed together with thediluents acetone and isopropyl alcohol. The suspension is then combinedwith the EUDRAGIT® polymer dispersions. The coating is sprayed onto thecore until approximately 10 mg/cm2 of polymer has been applied to thecore.

In at least one embodiment the controlled release coat is a polymerblend coating possessing pH dependent polymer (e.g. EUDRAGIT® L30D55) incombination with a sustained release polymer (e.g. AQUACOAT®). Such acoating formulation can comprise:

AQUACOAT ® about 21% by weight of coating suspension (ethylcellulose30%) EUDRAGIT ® L30 D 55 about 21% by weight of coating suspensionTriethyl citrate about 3% by weight of coating suspension Water about55% by weight of coating suspension Solids total = about 15.6% Polymercontent of about 12.6% suspension =

Application of the polymer blend coating can be as follows: Coatingapplied to a 10 mg/cm2 application of polymer to the drug core.

In at least one embodiment the controlled release coat is a drug coatingcontaining at least one other drug (e.g. Citalopram) on top of a corecontaining bupropion hydrobromide salt. The coating formulation cancomprise:

KOLLIDON ® VA64 about 2.5% by weight of drug coating(Vinylpyrrolidone-vinyl suspension acetate copolymer) KLUCEL ™ EF about2.5% by weight of drug coating (Hydroxypropylcellulose) suspensionCitalopram about 2% by weight of drug coating suspension Talc about 3%by weight of drug coating suspension 2-propanol about 90% by weight ofdrug coating suspension Solids total = about 10% Polymer content ofabout 5% suspension =

Application of the drug coating formulation can be as follows: Drugcoating is sprayed onto tablets until the desired amount of other drug(e.g. Citalopram) is applied.

A top-coat can subsequently be applied as a cosmetic coating and also toprevent tablet sticking.

The top-coat formulation applied to the drug coated core can comprise:

KOLLIDON ® VA64 about 2.5% by weight of top-coat suspension(Vinylpyrrolidone-vinyl acetate copolymer) KLUCEL ™ EF about 2.5% byweight of top-coat suspension (Hydroxypropylcellulose) Talc about 2.5%by weight of top-coat suspension Isopropyl alcohol about 92.5% by weightof top-coat suspension Solids total = about 7.5% Polymer content ofabout 5% suspension =

Application of the top-coating formulation can be as follows: Coating isapplied to about a 2% weight gain (expressed as % of drug coated tabletcore)

The Extended Release (XL) Controlled Release Coat

The XL controlled release coat is a semi-permeable coat comprising awater-insoluble, water-permeable film-forming polymer, a water-solublepolymer, and optionally a plasticizer.

Non-limiting examples of water-insoluble, water-permeable film-formingpolymers useful for the XL controlled release coat of certainembodiments include cellulose ethers, cellulose esters, polyvinylalcohol and mixtures thereof. In certain embodiments thewater-insoluble, water-permeable film forming polymers can be the ethylcelluloses, and can be selected from the following non-limitingexamples: ethyl cellulose grades PR100, PR45, PR20, PR10 and PR7(ETHOCEL®, Dow), and any combination thereof. In at least one embodimentof the invention, ethyl cellulose grade PR 100 is the water-insoluble,water-permeable film-forming polymer. In certain embodiments the amountof the water-insoluble water-permeable film-forming polymer can varyfrom about 1% to about 12% by weight of the tablet dry weight, includingall values and ranges therebetween . For example, in certain embodimentsthe amount of the water-insoluble water-permeable film-forming polymeris present in an amount from about 5% to about 10%, and in otherembodiments from about 6% to about 8% by weight of the tablet dryweight. In certain embodiments of the 174 mg dose modified-releasetablets of the invention, the amount of water-insoluble water permeablefilm-forming polymer is from about 3% to about 8% by weight of thetablet dry weight, preferably from about 6% to about 7% of the tabletdry weight, including all values and ranges therebetween . With respectto the controlled release coat itself, the amount of water-insolublewater-permeable film-forming polymer in certain embodiments of the 174mg dose tablet can be from about 35% to about 60% by weight of thecontrolled release coat dry weight, including all values and rangestherebetween; and in certain embodiments from about 40% to about 50% byweight of the controlled release coat dry weight. In certain embodimentsof the 348 mg dose modified-release tablet of the invention, the amountof water-insoluble water-permeable film-forming polymer can be fromabout 2% to about 5% by weight of the tablet dry weight, including allvalues and ranges therebetween, and in other embodiments from about 3%to about 4% by weight of the tablet dry weight. With respect to thecontrolled release coat itself, the water-insoluble water-permeablefilm-forming polymer in certain embodiments of the 348 mg dose tablet ispresent in an amount of about 40% by weight of the controlled releasecoat dry weight. In certain embodiments of the 522 mg dosemodified-release tablet of the invention, the amount of water-insolublewater-permeable film-forming polymer can be from about 0.5% to about 10%by weight of the tablet dry weight, including all values and rangestherebetween, and in other embodiments from about 1% to about 6% byweight of the tablet dry weight. With respect to the controlled releasecoat itself, the water-insoluble water-permeable film-forming polymer incertain embodiments of the 522 mg dose tablet is present in an amount ofabout 37% by weight of the controlled release coat dry weight.

Non-limiting examples of water-soluble polymers useful for the XLcontrolled release coat include polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropyl cellulose and mixtures thereof. In atleast one embodiment the water-soluble polymer is polyvinylpyrrolidone(POVIDONE® USP). The amount of water-soluble polymer can vary from about1.5% to about 10% by weight of the tablet dry weight, including allvalues and ranges therebetween. For example, in certain embodiments theamount of water-soluble polymer is from about 3% to about 8%, and inother embodiments at about 4% by weight of the tablet dry weight. Withrespect to the controlled release coat itself, in certain embodimentsthe amount of water-soluble polymer present is from about 25% to about55% by weight of the controlled release coat dry weight, including allvalues and ranges therebetween . For certain embodiments of the 174 mgdose of the extended release tablet of the invention, the amount ofwater-soluble polymer is from about 3% to about 5% by weight of thetablet dry weight, including all values and ranges therebetween and fromabout 25% to about 50% by weight of the controlled release coat dryweight, including all values and ranges therebetween. For certainembodiments of the 348 mg dose of the extended release tablet of theinvention, the amount of water-soluble polymer present is from about 2%to about 5% of the tablet dry weight including all values and rangestherebetween; and from about 40% to about 50% by weight of thecontrolled release coat dry weight, including all values and rangestherebetween. For certain embodiments of the 522 mg dose of the extendedrelease tablet of the invention, the amount of water-soluble polymerpresent is from about 2% to about 5% of the tablet dry weight, includingall values and ranges therebetween; and from about 40% to about 50% byweight of the controlled release coat dry weight, including all valuesand ranges therebetween .

In certain embodiments, the XL controlled release coat further comprisesa plasticizer. The use of plasticizers is optional, and they can beadded to film coating formulations to modify the physical properties ofa polymer to make it more usable during manufacturing. Plasticizers canbe high boiling point organic solvents used to impart flexibility tootherwise hard or brittle polymeric materials. Plasticizers generallycause a reduction in the cohesive intermolecular forces along thepolymer chains resulting in various changes in polymer propertiesincluding a reduction in tensile strength, and increase in elongationand a reduction in the glass transition or softening temperature of thepolymer. The amount and choice of the plasticizer can affect thehardness of a tablet and can even affect its dissolution ordisintegration characteristics, as well as its physical and chemicalstability. Certain plasticizers can increase the elasticity and/orpliability of a coat, thereby decreasing the coat's brittleness. Oncethe dosage form is manufactured, certain plasticizers can function toincrease the hydrophilicity of the coat(s) and/or the core of the dosageform in the environment of use (in-vitro or in-vivo). Non-limitingexamples of plasticizers that can be used in the controlled release coatdescribed herein include acetylated monoglycerides; acetyltributylcitrate, butyl phthalyl butyl glycolate; dibutyl tartrate; diethylphthalate; dimethyl phthalate; ethyl phthalyl ethyl glycolate; glycerin;propylene glycol; triacetin; tripropioin; diacetin; dibutyl phthalate;acetyl monoglyceride; acetyltriethyl citrate, polyethylene glycols;castor oil; rape seed oil, olive oil, sesame oil, triethyl citrate;polyhydric alcohols, glycerol, glycerin sorbitol, acetate esters,gylcerol triacetate, acetyl triethyl citrate, dibenzyl phthalate,dihexyl phthalate, butyl octyl phthalate, diisononyl phthalate, butyloctyl phthalate, dioctyl azelate, epoxidized tallate, triisoctyltrimellitate, diethylhexyl phthalate, di-n-octyl phthalate, di-i-octylphthalate, di-i-decyl phthalate, di-n-undecyl phthalate, di-n-tridecylphthalate, tri-2-ethylhexyl trimellitate, di-2-ethylhexyl adipate,di-2-ethylhexyl sebacate, di-2-ethylhexyl azelate, dibutyl sebacate,diethyloxalate, diethylmalate, diethylfumerate, dibutylsuccinate,diethylmalonate, dibutylphthalate, dibutylsebacate, glyceroltributyrate,polyols (e.g. polyethylene glycol) of various molecular weights, andmixtures thereof. It is contemplated and within the scope of theinvention, that a combination of plasticizers can be used in the presentformulation. In at least one embodiment of the invention, the plastizeris polyethylene glycol 4000, dibutyl sebacate or a mixture thereof. Theamount of plasticizer for the controlled release coat can vary in anamount of from about 0.5% to about 4% by weight of the tablet dryweight, including all values and ranges therebetween. For example, incertain embodiments the plasticizer is present in an amount of fromabout 2% to about 3% by weight of the tablet dry weight. For certainembodiments of the 174 mg dose extended-release tablet of the invention,the amount of plasticizer present in the controlled release coat is fromabout 1% to about 4% by weight of the tablet dry weight, including allvalues and ranges therebetween . For certain embodiments of the 348 mgdose extended release tablet of the invention, the amount of plasticizerpresent is from about 0.5% to about 4% by weight of the tablet dryweight, including all values and ranges therebetween. For certainembodiments of the 522 mg dose extended release tablet of the invention,the amount of plasticizer present is from about 0.5% to about 4% byweight of the tablet dry weight, including all values and rangestherebetween. In certain embodiments of the 174 mg, 348 mg and 522 mgdosage forms, the plasticizer is present in an amount of from about 6%to about 30% by weight of the controlled release coat dry weight,including all values and ranges therebetween. For example, in certainembodiments the plasticizer is present in an amount of about 12% byweight of the controlled release coat dry weight.

The ratio of water-insoluble water-permeable film formingpolymer:plasticizer:water-soluble polymer for the XL controlled releasecoat of certain embodiments of the invention described herein can varyfrom about 3:1:4 to about 5:1:2, including all values and rangestherebetween. For example, in certain embodiments the ratio ofwater-insoluble water-permeable film formingpolymer:plasticizer:water-soluble polymer for the XL controlled releasecoat is about 4:1:3. For certain other embodiments of the XL tablet theratio of the water-insoluble water-permeable film-formingpolymer:plasticizer:water-soluble polymer in the XL controlled releasecoat is from about 7:2:6 to about 19:5:18, including all values andranges therebetween. In at least one embodiment the ratio ofwater-insoluble water-permeable film formingpolymer:plasticizer:water-soluble polymer for the XL controlled releasecoat is about 13:4:12. In at least one embodiment of the 522 mg dosageform, the ratio of water-insoluble water-permeable film formingpolymer:plasticizer:water-soluble polymer for the XL controlled releasecoat is about 13:6:16.

In certain embodiments the XL controlled release coat of the bupropionhydrobromide tablet can be made according to any one of the methodsdescribed herein.

Preparation and application of the XL controlled release coat can be asfollows. The water-insoluble water-permeable film-forming polymer (e.g.ethylcellulose), and the plasticizer (e.g. polyethylene glycol 4000),are dissolved in an organic solvent (e.g. a mixture of ethyl alcohol).In the manufacture of embodiments that do not require a plasticizer, thewater-insoluble water-permeable film-forming polymer can be dissolved inthe organic solvent without the plasticizer. The water-soluble polymer(e.g. polyvinyl pyrrolidone) is next added until a homogenous mixture isachieved. The resulting controlled release coat solution is then sprayedonto the tablet cores using a tablet coater, fluidized bed apparatus orany other suitable coating apparatus known in the art until the desiredweight gain is achieved. The tablet cores coated with the controlledrelease coat are subsequently dried. In the manufacture of embodimentsthat have a moisture barrier, the controlled release coat is driedbefore the moisture barrier is applied.

An example of the coating process for the XL controlled release coat isas follows: The XL controlled release coat solution is prepared bydissolving the water insoluble polymer (e.g. ethylcellulose) and watersoluble polymer (e.g. polyvinylpyrrolidone) and an ethyl alcohol mixturewhile mixing and is followed with the addition of the plasticizer(s)(e.g. mixture of polyethylene glycol 4000 and dibutyl sebacate). Oncecompletely dissolved, the solution is homogenized to obtain a uniformmixture of appropriate viscosity. This procedure helps obtain a complexmix of a water permeable film to control the release of the active drug.The composition of the solution can be formulated to contain variouslevels of the water insoluble polymer and water soluble polymer and amix of the plasticizer(s). The release function is further controlled bythe film thickness applied and measured as weight gain of solids in thecoating required. Tablets are coated in a perforated coating pan withcontrol of pan speed (e.g. from about 8 rpm to about 14 rpm, includingall values and ranges therebetween; and in some cases about 12 rpm),spray rate (e.g. from about 150 gm/min to about 250 gm/min, includingall values and ranges therebetween; and in some cases about 200 gm/min),atomization pressure (e.g. from about 15 psi to about 25 psi, includingall values and ranges therebetween; and in some cases about 20 psi),supply volume (from about 800 to about 1000 cubic ft/min, including allvalues and ranges therebetween, and in some cases about 900 cubicft/min), and air temperature (e.g. from about 50° C. to about 60° C.,including all values and ranges therebetween; and in some cases about55° C.), monitored through a bed temperature and/or outlet temperatureof from about 38° C. to about 42° C., including all values and rangestherebetween; and in some cases about 40° C. On completion of thecoating cycle, tablets are dried and unloaded into bulk containers. Theprinting process comprises the transfer of a print image from a printplate covered with edible black ink and transferred via a print roll orprint pad onto the surface of the tablets. The printed tablets aretransferred through a drying element prior to discharging into bulkcontainers. Samples for final testing are taken throughout the printingprocess.

The skilled artisan will appreciate that controlling the permeabilitycan control the release of the bupropion hydrobromide salt and/or theamount of coating applied to the tablet cores. The permeability of theXL controlled release coat can be altered by varying the ratio of thewater-insoluble, water-permeable film-formingpolymer:plasticizer:water-soluble polymer and/or the quantity of coatingapplied to the tablet core. A more extended release can be obtained witha higher amount of water-insoluble, water-permeable film formingpolymer. The addition of other excipients to the tablet core can alsoalter the permeability of the controlled release coat. For example, ifit is desired that the tablet core further comprise an expanding agent,the amount of plasticizer in the controlled release coat could beincreased to make the coat more pliable, as the pressure exerted on aless pliable coat by the expanding agent could rupture the coat.Further, the proportion of the water-insoluble water-permeable filmforming polymer and water-soluble polymer can also be altered dependingon whether a faster or slower dissolution and/or release profile isdesired.

Depending on the dissolution or in-vivo release profile desired, theweight gained after coating the tablet core with the XL controlledrelease coat typically can vary from about 3% to about 30% of the weightof the dry tablet core, including all values and ranges therebetween .For a 174 mg dose extended release tablet according to certainembodiments, the weight gain can typically vary from about 10% to about17% of the weight of the dry tablet core, including all values andranges therebetween . For the 348 mg dose extended release tablet ofcertain embodiments, the weight gain can vary from about 7% to about 10%of the weight of the dry tablet core, including all values and rangestherebetween For the 522 mg dose extended release tablet of certainembodiments, the weight gain can vary from about 5% to about 15% of theweight of the dry tablet core, including all values and rangestherebetween

AQ Controlled Release Coat

The AQ controlled release coat is a stable monolithic controlled releasecoating comprising an aqueous dispersion of a neutral ester copolymerwithout any functional groups, a poly glycol having a melting pointgreater than about 55° C., and one or more pharmaceutically acceptableexcipients; wherein said coating composition is coated onto the dosageform and cured at a temperature at least equal to or greater than themelting point of the poly glycol. The coating formulation is quiteversatile in that it can be used to coat a variety of drug cores and canbe easily manipulated to obtain the desired drug release profile.

In certain other embodiments, the AQ controlled release coat comprisesan aqueous dispersion of an ethylcellulose, a poly glycol having amelting point greater than about 55° C., and one or morepharmaceutically acceptable excipients; wherein said coating compositionis coated onto the dosage form and cured at a temperature at least equalto or greater than the melting point of the poly glycol. Non limitingexamples of aqueous dispersions of an ethylcellulose include SURELEASE®(Colorcon, Inc., West Point, Pa., U.S.A.), and AQUACOAT® (FMC Corp.,Philadelphia, Pa., U.S.A.). Combinations are operable.

In certain embodiments the AQ controlled release coat is a stablecontrolled release monolithic coating that is formed by a process thatcomprises coating the core with a coating composition to form a coatedcore with an intermediate coating, and curing the coated core to formthe AQ controlled release coat. In at least one embodiment the coatingcomposition comprises an aqueous dispersion of a neutral ester copolymerwithout any functional groups, a poly glycol having a melting point ofat least 55° C., and one or more pharmaceutically acceptable excipients.The curing is conducted at a temperature at least equal to or greaterthan the melting point of the poly glycol. In at least one embodimentthe stable AQ controlled release coat comprises a neutral estercopolymer without any functional groups, a poly glycol having a meltingpoint of at least 55° C., and one or more pharmaceutically acceptableexcipients.

The aqueous dispersion of a neutral ester copolymer without anyfunctional groups can be an ethyl acrylate and methyl methacrylatecopolymer dispersion. Non-limiting examples of ethyl acrylate and methylmethacrylate copolymer dispersions include a 30% aqueous dispersion of aneutral copolymer based on ethyl acrylate and methyl methacrylate (e.g.EUDRAGIT® NE30D), a 40% aqueous dispersion of a neutral copolymer basedon ethyl acrylate and methyl methacrylate (e.g. EUDRAGIT® NE40D),EUDRAGIT® NM30D, KOLLICOAT® EMM30D, and combinations thereof. In atleast one embodiment the neutral ester copolymer without any functionalgroups used in the controlled release coating composition is EUDRAGIT®NE30D, EUDRAGIT® NE40D, or a mixture thereof. The neutral estercopolymer without any functional groups can be present in certainembodiments in an amount of from about 1% to about 35% by weight of thecoating composition, including all values and subranges therebetween,depending on the therapeutically active agent used and the controlledrelease profile desired. In certain embodiments the neutral estercopolymer without any functional groups is present in an amount fromabout 20% to about 99.5% by dry weight of the AQ controlled releasecoat, including all values and subranges therebetween. In otherembodiments the neutral ester copolymer without any functional groups ispresent in an amount from about 25% to about 60% by dry weight of the AQcontrolled release coat, including all values and subrangestherebetween. In still other embodiments the neutral ester copolymerwithout any functional groups is present in an amount from about 37% toabout 50% by dry weight of the AQ controlled release coat, including allvalues and subranges therebetween; for example, including about 38%,about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about45%, about 46%, about 47%, about 48%, and about 49% by dry weight of theAQ controlled release coat. In certain embodiments the neutral estercopolymer without any functional groups is present in the coatingcomposition in an amount of from about 0.4% to about 39.8% by dry weightof the tablet including all values and subranges therebetween; in otherembodiments in an amount of from about 0.8% to about 24.0% by dry weightof the tablet, including all values and subranges therebetween; and instill other embodiments in an amount of from about 2.0% to about 5.5% bydry weight of the tablet, including all values and subrangestherebetween.

Hydrophilic agents can also be included in the AQ controlled releasecoat to promote wetting of the coat when in contact withgastrointestinal fluids. Non-limiting examples of such hydrophilicagents include hydrophilic water soluble polymers such as hydroxypropylmethylcellulose (HPMC), hydroxypropyl cellulose (HPC) and combinationsthereof. In at least one embodiment, HPMC is the hydrophilic watersoluble polymer. If hydrophilic agents are to be included in the coatcomposition, the agents can be present in an amount from about 0.1% toabout 10% by weight of the coating composition, including all values andranges therebetween. For example, in certain embodiments the hydrophilicagents are present in an amount of from about 0.1% to about 5%, and inother embodiments from about 0.1% to about 3% by weight of thecontrolled release coat composition. In certain embodiments thehydrophilic agent is present in an amount of from greater than about 0%to about 35% by dry weight of the AQ controlled release coat, includingall values and subranges therebetween; preferably from about 8% to about30% by dry weight of the AQ controlled release coat, including allvalues and subranges therebetween and still further preferably fromabout 12% to about 26% by dry weight of the AQ controlled release coat,including all values and subranges therebetween. In certain embodimentsthe hydrophilic agent is present in the coating formulation in an amountof from about 0% to about 14.0% by dry weight of the tablet, includingall values and subranges therebetween; preferably from about 0.2% toabout 6.0% by dry weight of the tablet, including all values andsubranges therebetween; and still further preferably from about 0.8% toabout 2.5% by dry weight of the tablet, including all values andsubranges therebetween.

The AQ controlled release coat formulation also comprises a poly glycolwith a melting point of greater than about 55° C. The poly gycol used inthe AQ controlled release coat can be a polyethylene glycol with anaverage molecular weight ranging from about 4,000 daltons to about35,000 daltons. Non-limiting examples of a poly gycol with a meltingpoint of greater than 55° C. include polyethylene glycol 4000,polyethylene glycol 4600, polyethylene glycol 6000, polyethylene glycol8000, polyethylene glycol 10000, polyethylene glycol 12000, polyethyleneglycol 20000, polyethylene glycol 35000, and mixtures thereof. Incertain embodiments, the poly glycol is selected from the groupconsisting of polyethylene glycol 6000, polyethylene glycol 8000,polyethylene glycol 10000, polyethylene glycol 12000, and mixturesthereof. In at least one embodiment the poly glycol used in the coatingcomposition of the AQ controlled release coat is polyethylene glycol8000. The poly glycol can be present in certain embodiments in an amountof from about 0.1% to about 10% by weight of the coating composition,including all values and subranges therebetween. In certain embodimentsthe poly glycol is present in an amount of from about 0.5% to about 28%by dry weight of the AQ controlled release coat, including all valuesand subranges therebetween. In other embodiments the poly glycol ispresent in an amount from about 4% to about 17% by dry weight of the AQcontrolled release coat, including all values and subrangestherebetween. In still other embodiments the poly glycol is present inan amount from about 7.2% to about 15.2% by dry weight of the AQcontrolled release coat, including all values and subrangestherebetween; In certain embodiments the poly glycol is present in thecoating composition in an amount of from about 0.1% to about 11.2% bydry weight of the tablet, including all values and subrangestherebetween; in other embodiments in an amount of from about 0.1% toabout 8.0% by dry weight of the tablet, including all values andsubranges therebetween; and in still other embodiments in an amount offrom about 0.2% to about 2.8% by dry weight of the tablet, including allvalues and subranges therebetween. Other examples of suitable polyglycolderivatives having a melting point of at least about 55° C. include, butare not limited to, Poloxamer 188, Poloxamer 338, Poloxamer 407,Polyethylene Oxides, Polyoxyethylene Alkyl Ethers, PolyoxyethyleneStearates and mixtures thereof.

In addition to the copolymers and the poly glycol, the AQ controlledrelease coat formulation comprises at least one pharmaceuticallyacceptable excipient. The excipients can include but are not limited toanti-tacking agents, emulsifying agents, antifoaming agents,flavourants, colourants, and mixtures thereof. It is known in the artthat depending on the intended main function, excipients can affect theproperties of the coat in a series of ways, and many substances used incoat formulations can thus be described as multifunctional. A skilledworker will know, based on his technical knowledge, whichpharmaceutically acceptable excipients are suitable for the desired AQcontrolled release coat composition.

The tackiness of polymeric films is a factor for the coating of soliddosage forms and for the subsequent curing step (post coating thermaltreatment). During coating with either cellulosic or acrylic polymers,sometimes an unwanted agglomeration of several granules or beads canoccur, for example at higher product processing temperatures.Accordingly, the addition of anti-tacking agents to coating formulationscan be desirable in certain embodiments. The anti-tacking agents whichcan be used in certain embodiments include but are not limited to adipicacid, magnesium stearate, calcium stearate, zinc stearate, hydrogenatedvegetable oils, sterotex, glyceryl monostearate, talc (e.g. talc 400),sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, andmixtures thereof. In at least one embodiment, talc is the anti-tackingagent. Talc can also function as a wetting agent. Mixtures of theanti-tacking agents are operable. The amount of anti-tacking agent inthe controlled release coat composition can range from about 1% to about15% by weight of the controlled release coating composition, includingall values and ranges therebetween. For example, in certain embodimentsthe anti-tacking agent is present in an amount of from about 1% to about7% by weight of the controlled release coating composition. In certainembodiments the anti-tacking agent is present in an amount of fromgreater than about 0% to about 50% by dry weight of the AQ controlledrelease coat including all values and subranges therebetween; preferablyfrom about 2% to about 40% by dry weight of the AQ controlled releasecoat including all values and subranges therebetween and still furtherpreferably from about 10% to about 30% by dry weight of the AQcontrolled release coat including all values and subranges therebetween.In certain embodiments the anti-tacking agent is present in the coatingformulation in an amount of from about 0% to about 20.0% by dry weightof the tablet, including all values and subranges therebetween; in otherembodiments in an amount of from about 0% to about 12.0% by dry weightof the tablet, including all values and subranges therebetween; and instill other embodiments in an amount of from about 0.6% to about 7.0% bydry weight of the tablet, including all values and subrangestherebetween.

Certain embodiments can include anti-foaming agents in the AQ controlledrelease coat composition. Non-limiting examples of useful anti-foamingagents include silicon oil, simethicone, and mixtures thereof. In atleast one embodiment, simethicone is the anti-foaming agent used in theAQ controlled release coat composition. The anti-foaming agent can bepresent in an amount of up to about 0.5% by weight of the AQ controlledrelease coat composition. For example, in certain embodiment theanti-foaming agent is present in an amount of from about 0.1% to about0.4% by weight of the AQ controlled release coat composition, includingall values and ranges therebetween. In certain embodiments theanti-foaming agent is present in an amount of from greater than about 0%to about 3% by dry weight of the AQ controlled release coat, includingall values and subranges therebetween. In other embodiments theanti-foaming agent is present in an amount from about 0.4% to about 2%by dry weight of the AQ controlled release coat, including all valuesand subranges therebetween. In still other embodiments the anti-foamingagent is present in an amount from about 0.8% to about 1.5% by dryweight of the AQ controlled release coat, including all values andsubranges therebetween; for example, including about 0.9%, about 1.0%,about 1.1%, about 1.2%, about 1.3%, and about 1.4% by dry weight of theAQ controlled release coat. In certain embodiments the anti-foamingagent is present in the coating formulation in an amount of from about0% to about 1.2% by dry weight of the tablet, including all values andsubranges therebetween; in other embodiments in an amount of from about0% to about 0.8% by dry weight of the tablet, including all values andsubranges therebetween; and in still other embodiments in an amount offrom about 0% to about 0.2% by dry weight of the tablet, including allvalues and subranges therebetween; for example, including about 0.01%,about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about0.07%, about 0.08%, about 0.09%, about 0.10%, about 0.11%, about 0.12%,about 0.13%, about 0.14%, about 0.15%, about 0.16%, about 0.17%, about0.18%, and about 0.19% by dry weight of the tablet.

Certain embodiments can include emulsifying agents (also calledemulsifiers or emulgents) in the AQ controlled release coat. Emulsifyingagents can facilitate emulsification during manufacture of the AQcontrolled release coat, and also provide emulsion stability during theshelf-life of the product. Non-limiting examples of emulsifying agentsinclude naturally occurring materials and their semi syntheticderivatives, such as the polysaccharides, as well as glycerol esters,cellulose ethers, sorbitan esters and polysorbates. Mixtures areoperable. In at least one embodiment the emulsifying agent isPolysorbate 80 (polyoxyethylene sorbitan mono-oleate) (e.g. TWEEN® 80).The emulsifying agent can be present in an amount of from about 0% toabout 0.5% by weight of the AQ controlled release coat composition,including all values and subranges therebetween. For example, in certainembodiments the emulsifying agent is present in an amount of from about0.1% to about 0.3% by weight of the AQ controlled release coatcomposition, including all values and ranges therebetween. In certainembodiments the emulsifying agent is present in an amount of fromgreater than about 0% to about 2% by dry weight of the AQ controlledrelease coat, including all values and subranges therebetween. In otherembodiments the emulsifying agent is present in an amount from about0.1% to about 1% by dry weight of the AQ controlled release coat,including all values and subranges therebetween. In still otherembodiments the emulsifying agent is present in an amount from about0.25% to about 0.75% by dry weight of the AQ controlled release coat,including all values and subranges therebetween; for example, includingabout 0.30%, about 0.35%, about 0.40%, about 0.45%, about 0.50%, about0.55%, about 0.60%, about 0.65%, and about 0.70% by dry weight of the AQcontrolled release coat. In certain embodiments the emulsifying agent ispresent in the coating formulation in an amount of from greater thanabout 0% to about 0.8% by dry weight of the tablet, including all valuesand subranges therebetween; in other embodiments in an amount of fromgreater than about 0% to about 0.4% by dry weight of the tablet,including all values and subranges therebetween; and in still otherembodiments in an amount of from greater than about 0% to about 0.2% bydry weight of the tablet, including all values and subrangestherebetween; for example, including about 0.01%, about 0.02%, about0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%,about 0.09%, about 0.10%, about 0.11%, about 0.12%, about 0.13%, about0.14%, about 0.15%, about 0.16%, about 0.17%, about 0.18%, and about0.19% by dry weight of the tablet.

Certain embodiments can include colorants in the film coat formula. Suchcolorants can be water-insoluble colors (pigments). Pigments havecertain advantages over water-soluble colors in that they tend to bemore chemically stable towards light, provide better opacity andcovering power, and optimize the impermeability of a given film to watervapor. Non-limiting examples of suitable colorants include iron oxidepigments, titanium dioxide, and aluminum Lakes. Mixtures are operable.In at least one embodiment the pigment is titanium dioxide. The pigmentor colorant can be present in an amount of from about 0.1% to about 10%by weight of the AQ controlled release coat composition, including allvalues and ranges therebetween. For example, in certain embodiments thepigment or colorant is present in an amount of from about 0.1% to about5%, and in other embodiments from about 0.1% to about 2% by weight ofthe AQ controlled release coat composition. In certain embodiments thecolorant is present in an amount of from greater than about 0% to about20% by dry weight of the AQ controlled release coat, including allvalues and subranges therebetween. In other embodiments the colorant ispresent in an amount from greater than about 0% to about 10% by dryweight of the AQ controlled release coat, including all values andsubranges therebetween. In still other embodiments the colorant ispresent in an amount from about 2.2% to about 6.2% by dry weight of theAQ controlled release coat, including all values and subrangestherebetween. In certain embodiments the colorant is present in thecoating formulation in an amount of from greater than about 0% to about8.0% by dry weight of the tablet, including all values and subrangestherebetween; in other embodiments in an amount of from greater thanabout 0% to about 5.0% by dry weight of the tablet, including all valuesand subranges therebetween; and in still other embodiments in an amountof from greater than about 0% to about 1.0% by dry weight of the tablet,including all values and subranges therebetween; for example, includingabout 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%,about 0.7%, about 0.8%, and about 0.9% by dry weight of the tablet.

In at least one embodiment, the AQ controlled release coat hydrates whenplaced into water. In at least one embodiment the dosage form that iscoated with the AQ controlled release coat floats in water. In at leastone embodiment, the controlled release dosage form, upon oraladministration to a patient, provides controlled release of an effectiveamount of the bupropion hydrobromide to at least one region of thepatient's upper gastrointestinal tract (e.g. the stomach).

In certain embodiments the AQ controlled release coat is formed by aprocess that does not involve the use of an organic solvent. In suchembodiments the AQ controlled release coat composition is aqueous basedand not solvent based, in contrast to prior art coating compositionsthat are solvent based (e.g. “PharmaPASS” composition).

In certain embodiments the AQ controlled release coat of the bupropionhydrobromide tablet can be made according to any one of the methodsdescribed herein.

The AQ controlled release coat can be applied onto a core comprising aneffective amount of the bupropion hydrobromide salt by a process whichinvolves the atomization (spraying) of the coating solution orsuspension onto a bed of the tablet cores. Some examples of equipmentsuitable for film coating include: ACCELA COTA® (Manesty Machines,Liverpool, UK), HI-COATER® (Freund Company, Japan), DRIACOATER™ (DriamMetallprodukt GmbH, Germany), HTF/150 (GS, Italy), and IDA™ (Dumoulin,France). Examples of units that function on a fluidized-bed principleinclude: AEROMATIC™ (Fielder, Switzerland and UK) and GLATT™ AG(Switzerland). In at least one embodiment, the apparatus used for filmcoating is the ACCELA COTA®.

The coating fluid can be delivered to the coating apparatus from aperistaltic pump at the desired rate and sprayed onto the rotating orfluidizing tablet cores. The tablet cores are pre-warmed to about 30° C.During the coating process, the product temperature range is maintainedat from about 25° C. to about 35° C. by adjusting the flow rate of theinlet and outlet air, temperature of the inlet air and spray rate. Asingle layer of coat is applied and once spraying is complete, thecoated tablet cores are dried from about 30° C. to about 40° C. for atime period of from about 3 to about 5 minutes at a low pan speed andlow air flow. The pan is readjusted to jog speed, and drying continuesfor a time period of from about 12 to about 15 minutes.

The coated tablet cores are placed onto a tray and cured (post coatingthermal treatment) in an electrical or steam oven at a temperature abovethe temperature of the melting point of the polyethylene glycol orderivative thereof. In certain embodiments the curing temperature isgreater than the melting point of the polyethylene glycol or derivativethereof. In certain embodiments the curing time is from about 2 to about7 hours. The cured coated tablets are subsequently cooled to roomtemperature.

The AQ controlled release coat is quite versatile. The length and timefor the delay can be controlled by rate of hydration and the thicknessof the coat. The drug release rate subsequent to the delay can bedetermined by the thickness and permeability of the hydrated coat. Thus,it is possible to regulate the rate of hydration and permeability of theAQ controlled release coat so that the desired controlled-release drugprofile can be achieved. There is no preferred coat thickness, as thiswill depend on the controlled release profile desired. Other parametersin combination with the thickness of the coat include varying theconcentrations of some of the ingredients of the stable coat compositionof the invention described and/or varying the curing temperature andlength of curing the coated tablet cores. The skilled artisan will knowwhich parameters or combination of parameters to change for a desiredcontrolled release profile.

As will be seen from the non-limiting examples described herein, thecoatings used in certain embodiments of the present invention are quiteversatile. For example, the length and time for the lag time can becontrolled by the rate of hydration and the thickness of the controlledrelease coat. Other parameters in combination with the thickness of thecoatings include varying the concentrations of some of the ingredientsof the coating compositions of certain embodiments described and/orvarying the curing temperature and length of curing the coated tabletcores. The skilled artisan will know which parameters or combination ofparameters to change for a desired controlled release profile.

The Moisture Barrier Coat

In certain embodiments, an optional moisture barrier is applied directlyonto the controlled release coat. In other embodiments a moisturebarrier coat is not included in the dosage form. In certain embodimentsthe moisture barrier comprises an enteric polymer (e.g. acrylicpolymer), a permeation enhancer and optionally a plasticizer.

In certain embodiments, the enteric polymer is an acrylic polymer. Forexample, the acrylic polymer can be a methacrylic acid copolymer type C[poly(methacrylic acid, methyl methacrylate) 1:1] (e.g. EUDRAGIT® L 30D-55). The methacrylic acid copolymer can be present in an amount, whichcan vary from about 1% to about 3% of the tablet dry weight includingall values and ranges therebetween and from about 55% to about 70% ofthe moisture barrier dry weight including all values and rangestherebetween. For the 174 mg dose of the extended release tablet ofcertain embodiments of the present invention, the methacrylic acidcopolymer can vary from about 2% to about 3% of the tablet dry weightincluding all values and ranges therebetween. For example in the 174 mgtablet of certain embodiments, the amount of methacrylic acid copolymeris present in an amount of about 2.5% of the tablet dry weight. Withrespect to the moisture barrier itself, the amount of the methacrylicacid copolymer in the 174 mg tablet can be present in an amount of fromabout 55% to about 70% by weight of the moisture barrier dry weightincluding all values and ranges therebetween. For example, in the 174 mgtablet of certain embodiments the methacrylic acid copolymer is presentin an amount of about 60% of the moisture barrier dry weight. For the348 mg dose of the extended release tablet of certain embodiments, theamount of the methacrylic acid copolymer can vary from about 1.5% toabout 3% of the tablet dry weight including all values and rangestherebetween. For example, in the 348 mg tablet of certain embodiments,the amount of methacrylic acid copolymer is present at an amount ofabout 2% by weight of the tablet dry weight. With respect to themoisture barrier itself, the methacrylic acid copolymer in the 348 mgtablet typically will be present in an amount of from about 55% to about70% of the moisture barrier dry weight including all values and rangestherebetween. For example in certain embodiments of the 348 mg tabletthe methacrylic acid copolymer is present in an amount of about 60% ofthe moisture barrier dry weight. For the 522 mg dose of the extendedrelease tablet of certain embodiments, the amount of the methacrylicacid copolymer can vary from about 0.5% to about 5% of the tablet dryweight including all values and ranges therebetween. For example, in the522 mg tablet of certain embodiments, the amount of methacrylic acidcopolymer is present at about 2% by weight of the tablet dry weight.With respect to the moisture barrier itself, the methacrylic acidcopolymer in the 522 mg tablet typically will be present in an amount offrom about 40% to about 80% of the moisture barrier dry weight . Forexample, in certain embodiments of the 522 mg tablet the methacrylicacid copolymer is present in an amount of about 65% of the moisturebarrier dry weight.

It is known in the art that methacrylic acid copolymers can becomebrittle, and that coatings that contain methacrylic acid copolymerscould be made more elastic and pliable by the addition of a plasticizer.In certain embodiments the moisture barrier coat comprises aplasticizer. Non-limiting examples of plasticizers useful for themoisture barrier coat of certain embodiments include acetylatedmonoglycerides; acetyltributyl citrate, butyl phthalyl butyl glycolate;dibutyl tartrate; diethyl phthalate; dimethyl phthalate; ethyl phthalylethyl glycolate; glycerin; propylene glycol; triacetin; tripropioin;diacetin; dibutyl phthalate; acetyl monoglyceride; acetyltriethylcitrate, polyethylene glycols; castor oil; rape seed oil, olive oil,sesame oil, triethyl citrate; polyhydric alcohols, glycerol, glycerinsorbitol, acetate esters, gylcerol triacetate, acetyl triethyl citrate,dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, diisononylphthalate, butyl octyl phthalate, dioctyl azelate, epoxidized tallate,triisoctyl trimellitate, diethylhexyl phthalate, di-n-octyl phthalate,di-i-octyl phthalate, di-i-decyl phthalate, di-n-undecyl phthalate,di-n-tridecyl phthalate, tri-2-ethylhexyl trimellitate, di-2-ethylhexyladipate, di-2-ethylhexyl sebacate, di-2-ethylhexyl azelate, dibutylsebacate, diethyloxalate, diethylmalate, diethylfumerate,dibutylsuccinate, diethylmalonate, dibutylphthalate, dibutylsebacate,glyceroltributyrate, and mixtures thereof, polyols (e.g. polyethyleneglycol) of various molecular weights, and mixtures thereof. In certainembodiments, the plasticizer in the moisture barrier coat comprises acombination of triethyl citrate and polyethylene glycol 4000 (e.g.CARBOWAX® 4000). In certain of these embodiments, the ratio of triethylcitrate to polyethylene glycol 4000 is about 1:2. The plasticizer can bepresent in the moisture barrier coat of certain embodiments in an amountwhich can vary from about 0.2% to about 0.5%, including all values andranges therebetween (e.g. including about 0.3%, and about 0.4% of thetablet dry weight). For example in certain embodiments the plasticizercan be present in an amount of about 0.35% of the tablet dry weight fora 174 mg tablet; in an amount of from about 0.2% to about 0.4% of thetablet dry weight for a 348 mg tablet; and in an amount of from about0.05% to about 0.5% of the tablet dry weight for a 522 mg tablet,including all values and ranges therebetween. With respect to themoisture barrier itself, the plasticizer if present in certainembodiments can be present in an amount of from about 1% to about 30% byweight of the moisture barrier dry weight, including all values andranges therebetween. For example, in certain embodiments the plasticizeris present in an amount of from about 10% to about 14% of the moisturebarrier dry weight for the 174 mg, 348 mg and 522 mg dose extendedrelease tablet of the present invention. It is well known in the artthat depending on the intended main function, excipients to be used intablets are subcategorized into different groups. However, one excipientcan affect the properties of a drug or the tablet as a whole in a seriesof ways, and many substances used in tablet formulations can thereforebe described as multifunctional. For example, the polyethylene glycolused in the plasticizer combination for the moisture barrier can servenot only to increase the hydrophilicity of the moisture barrier, but canalso act as a glidant.

In certain embodiments the moisture barrier can further comprise apermeation enhancer that can increase its hydrophilicity, and can alsoact as a glidant. The permeation enhancer can be a hydrophilic substanceand can be selected from the following non-limiting examples:hydrophilic polymers such as hydroxypropylmethylcellulose, celluloseethers and protein-derived materials of these polymers, the celluloseethers, such as hydroxyalkylcelluloses, carboxyalkylcelluloses, andmixtures thereof. Also, synthetic water-soluble polymers can be used,such as polyvinylpyrrolidone, cross-linked polyvinyl-pyrrolidone,polyethylene oxide, water-soluble polydextrose, saccharides andpolysaccharides, such as pullulan, dextran, sucrose, glucose, lactose,fructose, mannitol, mannose, galactose, sorbitol and mixtures thereof.In at least one embodiment of the present invention, the hydrophilicpolymer comprises hydroxypropyl-methylcellulose. Other non-limitingexamples of permeation enhancers that can be used in the moisturebarrier of certain embodiments include alkali metal salts such asaluminum oxidelithium carbonate, sodium chloride, sodium bromide,potassium chloride, potassium sulfate, potassium phosphate, sodiumacetate, sodium citrate, and mixtures thereof. The permeation enhancersor pore-formers, can also be polymers which are soluble in theenvironment of use, such as CARBOWAX®, CARBOPOL®, and mixtures thereof.Non-limiting examples of pore formers include diols, polyols, polyhydricalcohols, polyalkylene glycols, polyglycols, poly(a-w)alkylenediols, andmixtures thereof. Other permeation enhancers which can be useful in theformulations of the present invention include starch, modified starch,and starch derivatives, gums, including but not limited to xanthan gum,alginic acid, other alginates, benitonite, veegum, agar, guar, locustbean gum, gum arabic, quince psyllium, flax seed, okra gum,arabinoglactin, pectin, tragacanth, scleroglucan, dextran, amylose,amylopectin, dextrin, cross-linked polyvinylpyrrolidone, ion-exchangeresins, such as potassium polymethacrylate, carrageenan,kappa-carrageenan, lambda-carrageenan, gum karaya, biosynthetic gum, andmixtures thereof. Other permeation enhancers include materials usefulfor making microporous lamina in the environment of use, such aspolycarbonates comprised of linear polyesters of carbonic acid in whichcarbonate groups reoccur in the polymer chain, microporous materialssuch as bisphenol, a microporous poly(vinylchloride), micro-porouspolyamides, microporous modacrylic copolymers, microporousstyrene-acrylic and its copolymers, porous polysulfones, halogenatedpoly(vinylidene), polychloroethers, acetal polymers, polyesters preparedby esterification of a dicarboxylic acid or anhydride with an alkylenepolyol, poly(alkylenesulfides), phenolics, polyesters, asymmetric porouspolymers, cross-linked olefin polymers, hydrophilic microporoushomopolymers, copolymers or interpolymers having a reduced bulk density,and other similar materials, poly(urethane), cross-linked chain-extendedpoly(urethane), poly(imides), poly(benzimidazoles), collodion,regenerated proteins, semi-solid cross-linked poly(vinylpyrrolidone),silicon dioxide, colloidal silica, microcrystalline cellulose and anycombination thereof. In at least one embodiment of the invention thepermeation enhancer is silicon dioxide (e.g. SYLOID® 244FP). The amountof permeation enhancer can vary from about 0.5% to about 1% by weight ofthe tablet dry weight including all values and ranges therebetween andfrom about 25% to about 30% by weight of the moisture barrier dry weightincluding all values and ranges therebetween. For the 174 mg doseextended-release tablet or the 348 mg dose extended-release tablet ofcertain embodiments of the invention, the permeation enhancer can bepresent in an amount of about 0.5% to about 2% of the tablet dry weightincluding all values and ranges therebetween and from about 20% to about40% by weight of the moisture barrier dry weight including all valuesand ranges therebetween For example, in certain embodiments of the 174mg dose tablet, the permeation enhancer is present in an amount of fromabout 25% to about 30% by weight of the moisture barrier dry weight. Forthe 348 mg dose extended release tablet of the invention, the permeationenhancer can be present in an amount which can vary from about 0.5% toabout 2% by weight of the tablet dry weight, and from about 20% to about40% by weight of the moisture barrier dry weight. For example, incertain embodiments of the 348 mg dose tablet, the permeation enhanceris present in an amount of from about 25% to about 30% by weight of themoisture barrier dry weight. For the 522 mg dose extended release tabletof the invention, the permeation enhancer can be present in an amountwhich can vary from about 0.1% to about 2% by weight of the tablet dryweight including all values and ranges therebetween, and from about 20%to about 40% by weight of the moisture barrier dry weight including allvalues and ranges therebetween. For example, in certain embodiments ofthe 522 mg dose tablet, the permeation enhancer is present in an amountof from about 25% to about 30% by weight of the moisture barrier dryweight.

In at least one embodiment of the invention, the ratio of themethacrylic acid copolymer:plasticizer:permeation enhancer in themoisture barrier is about 13:2:5.

In certain embodiments the moisture barrier of the bupropionhydrobromide dosage form can be made according to any one of the methodsdescribed herein.

The preparation and application of the moisture barrier process can beas follows. The optional plasticizer (e.g. a combination of polyethyleneglycol 4000 and triethyl citrate), can be first added to water and themixture mixed to homogeneity. The methacrylic acid co-polymer (e.g.EUDRAGIT® L 30 D-55), is next sieved and added to the plasticizermixture and mixed to homogeneity. In a separate container the permeationenhancer (e.g. silicon dioxide) is dissolved in water until ahomogeneous mixture is achieved. The plasticizer and methacrylic acidcopolymer mixture is then combined with the permeation enhancer solutionand mixed to homogeneity. The resulting moisture barrier solution isthen sprayed onto the tablet cores coated with the controlled releasecoat using a tablet coater, fluidized bed apparatus or any othersuitable coating apparatus known in the art until the desired weightgain is achieved. The tablets coated with the moisture barrier aresubsequently dried prior to packaging.

The moisture barrier is applied to the controlled release coated tabletcores such that the weight gain is not more than about 6% of the tabletdry weight for the 174 mg, 348 mg and 522 mg extended release tablets ofcertain embodiments of the present invention. In certain embodiments theweight gain is not more than about 3.5% of the tablet dry weight for the174 mg, 348 mg and 522 mg extended release tablets. The amount of themoisture barrier applied typically does not significantly render theextended release tablet described herein more resistant to gastricfluid. However, in certain embodiments the moisture barrier can have animpact on the drug release characteristics.

The moisture barrier as used in certain embodiments, does not functionas an enteric coat. Even though the methacrylic acid copolymer,EUDRAGIT® L 30 D-55, is referenced and is used in enteric coatingformulations in the art, its functionality is formulation dependent andon the quantity of the material applied. As is known in the art, anenteric coating is applied where a drug may be destroyed or inactivatedby gastric juice or where the drug may irritate the gastric mucosa. Tomeet the requirements for an enteric coat, the test as described in theUSP (method A or B) stipulates that after 2 hours in acidic media (e.g.0.1N HCl), no individual values of at least six experiments exceed about10% of the active drug dissolved and not less than about 75% dissolvedat about 45 minutes in pH about 6.8. The moisture barrier of certainembodiments does not meet this requirement for the following reasonseven though the bupropion hydrobromide salt is not negatively affectedin acidic media nor is it irritating the gastric mucosa: (1) to obtainenteric integrity with a film containing EUDRAGIT® L 30 D-55, a weightgain of from about 6% to about 8% based on the dry polymer per dosageunit is recommended. The amount of EUDRAGIT® L 30 D-55 solid appliedonto the controlled release coated tablet cores is not more than about6%, and in at least one embodiment, is not more than about 3%, (2) ifenteric integrity would be required, the dissolution test for thefinished product (i.e., the moisture barrier coated tablet cores) at the2 hour time point would not stipulate a limit of no more than about 20%,and (3) analytical tests performed on these coatings indicate that thecoatings do not meet all the test requirements as an enteric coatedproduct as defined by USP test methods.

The XL tablet of certain embodiments of the invention provides anextended release of the bupropion hydrobromide salt. In at least oneembodiment no pore forming agent is present in the XL coatingformulation. An extended release bupropion hydrobromide formulation isprovided in certain embodiments such that after about 2 hours, not morethan about 20% of the bupropion hydrobromide content is released. Forexample, in certain embodiments, from about 2% to about 18%, preferablyfrom about 4% to about 8%, or about 5% of the bupropion hydrobromidecontent is released after about 2 hours. After about 4 hours, from about15% to about 45% of the bupropion hydrobromide content is released. Forexample, in certain embodiments from about 21% to about 37%, morepreferably from about 28% to about 34%, or about 32% of the bupropionhydrobromide content is released after about 4 hours. After about 8hours, about 40% to about 90% of the bupropion hydrobromide content isreleased. For example, in certain embodiments from about 60% to about85%, from about 68% to about 74%, or about 74% of the bupropionhydrobromide content is released after about 8 hours. After about 16hours not less than about 80% of the bupropion hydrobromide content isreleased. For example, in certain embodiments of the bupropionhydrobromide content is released after about 16 hours.

Also, extended release tablets are provided in certain embodimentswherein after about 2 hours not more than about 40% (e.g., about 33%) ofthe bupropion hydrobromide is released; after about 4 hours from about40 to about 75% of the bupropion hydrobromide is released (e.g., about59%); after about 8 hours at least about 75% of the bupropionhydrobromide is released (e.g., about 91%); and after about 16 hours atleast about 85% of the bupropion hydrobromide is released (e.g., about97%). In all instances herein when actual or prophetic dissolutionprofiles are provided this means that the medicament possesses such aprofile in at least one dissolution medium under prescribed conditionssuch as are identified herein and are well known to those skilled in theart. Such dissolution media, dissolution conditions and apparatus foruse therein are disclosed in the United States Pharmacopoeia (USP) andEuropean and Japanese counterparts thereof. Additionally, specificexamples thereof are provided in this application.

Enhanced Absorption (EA) Tablets

In certain embodiments of the present invention, there is provided anenhanced absorption (EA) tablet having a core comprising a bupropionhydrobromide salt and conventional excipients, wherein the bupropionhydrobromide salt provides for the reduction of incidences of and/orseverity of bupropion-induced seizures, and is more stable, as comparedwith equivalent molar amounts of bupropion hydrochloride. The core issurrounded by an EA coating, which controls the release of the bupropionhydrobromide salt. In certain embodiments, the EA coating consists ofone coat. An advantage of the EA tablet includes the lower amount ofdrug required in the composition to be an effective amount, which inturn can lead to a reduction of side effects. The EA tablet optionallycan comprise one or more additional functional or non-functional coatssurrounding the core or EA coating.

The EA Core

The core of the EA tablet comprises an effective amount of a bupropionhydrobromide salt, a binder and a lubricant, and can contain otherconventional inert excipients. In certain embodiments the core of the EAtablet can comprise the same excipients as, and can be processed in thesame manner as the core of the extended release tablet. The amount ofthe bupropion hydrobromide salt present in the EA core can vary fromabout 40% to about 99% by weight of the EA tablet dry weight, includingall values and ranges therebetween. The EA tablet comprises an effectiveamount of bupropion hydrobromide salt that can vary from about 50 mg toabout 1000 mg, including 100, 150, 200, 250, 300, 350, 400, 450, 500,510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 650, 700, 750, 800,85, 900, 950 mg and all values and ranges therebetween. For example,certain embodiments of the EA tablet can comprise about 150 mg, about300 mg or about 450 mg of bupropion hydrobromide. For a 150 mg dosetablet the bupropion hydrobromide can be present in an amount of fromabout 76% to about 84% by weight of the tablet dry weight. For a 300 mgdose, the amount of bupropion hydrobromide can be present in an amountof from about 80% to about 83% by weight of the tablet dry weight. For a450 mg dose, the amount of bupropion hydrobromide can be present in anamount of from about 75% to about 90% by weight of the tablet dryweight. For the 150 mg, 300 mg and 450 mg dose bupropion hydrobromide EAtablets of certain embodiments of the invention, the amount of bupropionhydrobromide can be present at about 94% by weight of the dry core foreach dose.

The EA Tablet Coating

The EA tablet cores can be coated in one stage. The EA coating isapplied directly onto the surface of the tablet cores and functions tocontrol the release of the bupropion hydrobromide salt. The EA coatingis a semi-permeable coat comprising a water-insoluble, water-permeablefilm-forming polymer, a water-soluble polymer, and optionally aplasticizer. In certain embodiments the EA coating can comprise the sameingredients as, and can be processed in the same manner as the XLcontrolled release coat.

Non-limiting examples of water-insoluble, water-permeable film-formingpolymers useful for the EA coating include those that can be used in theXL controlled release coat. The amount of the water-insolublewater-permeable film-forming polymer can vary from about 1% to about 8%by weight of the tablet dry weight, including all values and rangestherebetween. For example, in certain embodiments the amount of thewater-insoluble water-permeable film-forming polymer is from about 2% toabout 6% by weight of the tablet dry weight. For certain embodiments ofthe 150 mg, 300 mg or 450 mg dose EA tablets of certain embodiments ofthe invention, the amount of water-insoluble water permeablefilm-forming polymer is from about 1% to about 15% by weight of thetablet dry weight. For example, in certain embodiments of the 150 mgdose EA tablets, the amount of the water-insoluble water-permeablefilm-forming polymer is present at about 10.5% by weight of the tabletdry weight. With respect to the EA coat itself, the amount ofwater-insoluble water-permeable film-forming polymer in certainembodiments of the 150 mg dose EA tablets is from about 35% to about 60%by weight of the EA coat dry weight. For example, in certain embodimentsof the 150 mg dose EA tablet, the amount of water-insolublewater-permeable polymer is present at about 55% by weight of the EA coatdry weight. For certain embodiments of the 300 mg dose EA tablet of theinvention, the amount of water-insoluble water-permeable film-formingpolymer is from about 1% to about 8% by weight of the tablet dry weight.For example, in certain embodiments of the 300 mg dose EA tablet, theamount of water-insoluble water-permeable film forming polymer ispresent at about 6.3% by weight of the tablet dry weight. With respectto the EA coat itself, the water-insoluble water-permeable film-formingpolymer in the 300 mg dose EA tablet can be present in an amount ofabout 55% by weight of the EA coat dry weight. For certain embodimentsof the 450 mg dose EA tablet of the invention, the amount ofwater-insoluble water-permeable film-forming polymer is from about 0.5%to about 10% by weight of the tablet dry weight, and in otherembodiments is from about 1% to about 6% by weight of the tablet dryweight. With respect to the EA coat itself, the water-insolublewater-permeable film-forming polymer in the 450 mg dose EA tablet can bepresent in an amount of about 37% by weight of the EA coat dry weight.

In certain embodiments, the EA coat further comprises a plasticizer.Non-limiting examples of plasticizers that can be used in the EA coatinclude those that can be used in the XL controlled release coat. Theamount of plasticizer that can be used in the EA coat can vary in anamount from about 0.5% to about 4% by weight of the tablet dry weight,including all values and ranges therebetween. In a further embodiment ofthe invention, when a mixture of two plasticizers is used, the ratio ofthe two plasticizers can range from about 5:95 to about 95:5, includingall values and ranges therebetween. In at least one embodiment of theinvention, the plasticizer is polyethylene glycol 4000, dibutylsebacate, or a mixture thereof. The ratio of polyethylene glycol4000:dibutyl sebacate can range from about 5:95 to about 95:5. Forcertain embodiments of the 150 mg dose EA tablet of the invention, theamount of plasticizer present in the EA coat is from about 0.5% to about4% by weight of the tablet dry weight. For example, in certainembodiments of the 150 mg dose EA tablet, the amount of plasticizer ispresent at about 3.1% by weight of the tablet dry weight. For certainembodiments of the 300 mg dose EA tablet of the invention, the amount ofplasticizer present is from about 0.5% to about 3% by weight of thetablet dry weight. For example, in certain embodiments of the 300 mgdose EA tablet, the amount of plasticizer is present at about 2.0% byweight of the tablet dry weight. For certain embodiments of the 450 mgdose EA tablet of the invention, the amount of plasticizer present isfrom about 0.5% to about 4% by weight of the tablet dry weight. Forcertain embodiments of the 150 mg, 300 mg and 450 mg dosage forms, theplasticizer is present in an amount of from about 6% to about 30% byweight of the EA coat dry weight. For example, in certain embodimentsthe amount of plasticizer is present at about 17% by weight of the EAcoat dry weight

Non-limiting examples of water-soluble polymers useful for the EA coatinclude those that can be used in the XL controlled release coat. In atleast one embodiment of the invention, the water-soluble polymer ispolyvinylpyrrolidone (e.g. Povidone® USP) the amount of which can varyfrom about 1.5% to about 10% by weight of the tablet dry weight,including all values and ranges therebetween. With respect to the EAcoat itself, the amount of water-soluble polymer present can vary fromabout 20% to about 50% by weight of the EA coat dry weight. For certainembodiments of the 150 mg dose of the EA tablet of the invention, theamount of water-soluble polymer present is from about 1.5% to about 10%by weight of the tablet dry weight or from about 20% to about 50% byweight of the EA coat dry weight. For example, in certain embodiments ofthe 150 mg dose EA tablet, the water-soluble polymer is present in anamount of about 28% by weight of the EA coat dry weight. For certainembodiments of the 300 mg dose of the EA tablet of the invention, theamount of water-soluble polymer present is from about 1.5% to about 10%of the tablet dry weight and from about 20% to about 50% by weight ofthe EA coat dry weight. For example, in certain embodiments of the 300mg dose EA tablet, the water-soluble polymer is present in an amount ofabout 28% by weight of the EA coat dry weight. For certain embodimentsof the 450 mg dose of the EA tablet of the invention, the amount ofwater-soluble polymer present is from about 2% to about 5% of the tabletdry weight and from about 40% to about 50% by weight of the EA coat dryweight.

The ratio of water-insoluble water-permeable film formingpolymer:plasticizer:water-soluble polymer for the EA tablet coatingtypically will vary from about 3:1:4 to about 5:1:2, including allvalues and ranges therebetween. For example in certain embodiments theratio of water-insoluble water-permeable film formingpolymer:plasticizer:water-soluble polymer for the EA tablet coating isabout 4:1:3. In at least one embodiment of the EA tablet coating, theratio of the water-insoluble water-impermeable film-formingpolymer:plasticizer:water-soluble polymer is from about 7:2:6 to about19:5:18, and in another embodiment is about 13:4:12. In at least oneembodiment of the 450 mg dosage form, the ratio of water-insolublewater-permeable film forming polymer:plasticizer:water-soluble polymerfor the EA coating is about 13:6:16.

In certain embodiments the EA coat of the bupropion hydrobromide dosageform can be made according to any one of the methods described for theXL controlled release coat.

Depending on the dissolution or in-vivo release profile desired, theweight gained after coating the tablet core with the EA coat can varyfrom about 3% to about 30% of the weight of the dry tablet core,including all values and ranges therebetween. For certain embodiments ofthe 150 mg dose EA tablet of the invention the weight gain is from about8% to about 20% of the weight of the dry tablet core. For example, incertain embodiments of the 150 mg dose EA tablet, the weight gain isabout 14% of the weight of the dry tablet core. For certain embodimentsof the 300 mg dose EA tablet of the invention the weight gain is fromabout 10% to about 15% of the weight of the dry tablet core. Forexample, in certain embodiments of the 300 mg dose EA tablet, the weightgain is about 13% of the weight of the dry tablet core. For certainembodiments of the 450 mg dose EA tablet of the invention the weightgain is from about 5% to about 15% of the weight of the dry tablet core.For example, in certain embodiments of the 450 mg dose EA tablet, theweight gain is about 8.5% of the weight of the dry tablet core.

The EA tablet provides an enhanced-absorption of the bupropionhydrobromide salt wherein typically no pore forming agent is present inthe formulation. An enhanced absorption bupropion hydrobromideformulation is provided such that after about 2 hours, not more thanabout 25% of the bupropion hydrobromide content is released. Forexample, in certain embodiments from about 10% to about 20% of thebupropion hydrobromide content is released after about 2 hours. Afterabout 4 hours, from about 25% to about 55% of the bupropion hydrobromidecontent is released. For example, in certain embodiments from about 30%to about 50% of the bupropion hydrobromide content is released afterabout 4 hours. After about 8 hours, more than about 60% of the bupropionhydrobromide content is released. For example, in certain embodimentsfrom about 70% to about 90% of the bupropion hydrobromide content isreleased after about 8 hours. After about 16 hours more than about 70%of the bupropion hydrobromide content is released. For example, incertain embodiments more than about 80% of the bupropion hydrobromidecontent is released after about 16 hours.

In certain embodiments an enhanced absorption formulation is providedwherein not more than about 40% is released after about 2 hours; afterabout 4 hours from about 40% to about 75% is released; after about 8hours at least about 75% is released; and after about 16 hours at leastabout 85% is released. For example, in at least one embodiment, thebupropion hydrobromide release profile is about 33% after about 2 hours;about 59% after about 4 hours; about 91% after about 8 hours; and about97% after about 16 hours.

Controlled Release Matrix

In other embodiments of the present invention, a controlled releasematrix is provided from which the kinetics of drug release from thematrix core are dependent at least in part upon the diffusion and/orerosion properties of excipients within the composition. In thisembodiment controlled release matrices contain an effective amount of abupropion hydrobromide salt and at least one pharmaceutically acceptableexcipient. The amount of the bupropion hydrobromide salt present in thecontrolled release matrix can vary in an amount of from about 40% toabout 90% by weight of the matrix tablet dry weight, including allvalues and ranges therebetween. For example, in certain embodimentsbupropion hydrobromide is present in an amount from about 60% to about80%, and in other embodiment at about 70% by weight of the matrix tabletdry weight. The controlled release matrix can be multiparticulate oruniparticulate, and can be coated with at least one functional ornon-functional coating, or an immediate release coating containinganother drug. Functional coatings include by way of example controlledrelease polymeric coatings, enteric polymeric coatings, and the like.Non-functional coatings are coatings that do not affect drug release butwhich affect other properties (e.g., they can enhance the chemical,biological, or the physical appearance of the controlled releaseformulation). Those skilled in the pharmaceutical art and the design ofmedicaments are well aware of controlled release matrices conventionallyused in oral pharmaceutical compositions adopted for controlled releaseand means for their preparation.

Suitable excipient materials for use in such controlled release matricesare known by those of skill in the art, and include, by way of example,release-resistant or controlled release materials such as hydrophobicpolymers, hydrophilic polymers, lipophilic materials and mixturesthereof. Non-limiting examples of hydrophobic, or lipophilic componentsinclude glyceryl monostearate, mixtures of glyceryl monostearate andglyceryl monopalmitate (MYVAPLEX™, Eastman Fine Chemical Company),glycerylmonooleate, a mixture of mono, di and tri-glycerides (ATMUL™84S), glycerylmonolaurate, paraffin, white wax, long chain carboxylicacids, long chain carboxylic acid esters, long chain carboxylic acidalcohols, and mixtures thereof. The long chain carboxylic acids cancontain from about 6 to about 30 carbon atoms; in certain embodiments atleast about 12 carbon atoms, and in other embodiments from about 12 toabout 22 carbon atoms. In some embodiments this carbon chain is fullysaturated and unbranched, while others contain one or more double bonds.In at least one embodiment the long chain carboxylic acids contain about3-carbon rings or hydroxyl groups. Non-limiting examples of saturatedstraight chain acids include n-dodecanoic acid, n-tetradecanoic acid,n-hexadecanoic acid, caproic acid, caprylic acid, capric acid, lauricacid, myristic acid, palmitic acid, stearic acid, arachidic acid,behenic acid, montanic acid, melissic acid and mixtures thereof. Alsouseful are unsaturated monoolefinic straight chain monocarboxylic acids.Non-limiting examples of these include oleic acid, gadoleic acid, erucicacid and mixtures thereof. Also useful are unsaturated (polyolefinic)straight chain monocaboxyic acids. Non-limiting examples of theseinclude linoleic acid, linolenic acid, arachidonic acid, behenolic acidand mixtures thereof. Useful branched acids include, for example,diacetyl tartaric acid. Non-limiting examples of long chain carboxylicacid esters include glyceryl monostearates; glyceryl monopalmitates;mixtures of glyceryl monostearate and glyceryl monopalmitate (MYVAPLEX™600, Eastman Fine Chemical Company); glyceryl monolinoleate; glycerylmonooleate; mixtures of glyceryl monopalmitate, glyceryl monostearateglyceryl monooleate and glyceryl monolinoleate (MYVEROL™ 18-92, EastmanFine Chemical Company); glyceryl monolinolenate; glyceryl monogadoleate;mixtures of glyceryl monopalmitate, glyceryl monostearate, glycerylmonooleate, glyceryl monolinoleate, glyceryl monolinolenate and glycerylmonogadoleate (MYVEROL™ 18-99, Eastman Fine Chemical Company);acetylated glycerides such as distilled acetylated monoglycerides(MYVACET™ 5-07, 7-07 and 9-45, Eastman Fine Chemical Company); mixturesof propylene glycol monoesters, distilled monoglycerides, sodiumstearoyl lactylate and silicon dioxide (MYVATEX™ TL, Eastman FineChemical Company); mixtures of propylene glycol monoesters, distilledmonoglycerides, sodium stearoyl lactylate and silicon dioxide (MYVATEX™TL, Eastman Fine Chemical Company) d-alpha tocopherol polyethyleneglycol 1000 succinate (Vitamin E TPGS, Eastman Chemical Company);mixtures of mono- and diglyceride esters such as ATMUL™ (Humko ChemicalDivision of Witco Chemical); calcium stearoyl lactylate; ethoxylatedmono- and di-glycerides; lactated mono- and di-glycerides; lactylatecarboxylic acid ester of glycerol and propylene glycol; lactylic estersof long chain carboxylic acids; polyglycerol esters of long chaincarboxylic acids, propylene glycol mono- and di-esters of long chaincarboxylic acids; sodium stearoyl lactylate; sorbitan monostearate;sorbitan monooleate; other sorbitan esters of long chain carboxylicacids; succinylated monoglycerides; stearyl monoglyceryl citrate;stearyl heptanoate; cetyl esters of waxes; cetearyl octanoate; C10-C30cholesterol/lavosterol esters; sucrose long chain carboxylic acidesters; and mixtures thereof. The alcohols useful as excipient materialsfor controlled release matrices can include the hydroxyl forms of thecarboxylic acids exemplified above and also cetearyl alcohol.

In addition, waxes can be useful alone or in combination with thematerials listed above, as excipient materials for the controlledrelease matrix embodiments of the present invention. Non-limitingexamples of these include white wax, paraffin, microcrystalline wax,carnauba wax, and mixtures thereof.

The lipophilic agent can be present in an amount of from about 5% toabout 90% by weight of the controlled release matrix dosage form,including all values and ranges therebetween. For example, in certainembodiments the lipophilic agent is present in an amount of from about10% to about 85%, and in other embodiments from about 30% to about 60%by weight of the controlled release matrix dosage form.

Non-limiting examples of hydrophilic polymers that can be used incertain embodiments of the controlled release matrix dosage form includehydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC),hydroxyethylcellulose (HEC), carboxymethylcellulose (CMC) or othercellulose ethers, polyoxyethylene, alginic acid, acrylic acidderivatives such as polyacrylic acid, CARBOPOL™, polymethacrylatepolymer such as EUDRAGIT® RL, RS, R, S, NE and E, acrylic acid polymer,methacrylic acid polymer, hydroyethyl methacrylic acid (HEMA) polymer,hydroxymethyl methacrylic acid (HMMA) polymer, polyvinyl alcohols andmixtures thereof.

The hydrophilic polymer can be present in an amount of from about 10% toabout 90% by weight of the controlled release matrix dosage form,including all values and ranges therebetween. For example, in certainembodiments the hydrophilic polymer is present in an amount of fromabout 20% to about 75%, and in other embodiments from about 30% to about60% by weight of the controlled release matrix dosage form.

In at least one embodiment, the controlled release matrix dosage formcomprises hydroxypropylmethylcellulose (HPMC). Non-limiting examples ofhydroxypropyl methylcelluloses that can be used include METHOCEL® E (USPtype 2910), METHOCEL® F (USP type 2906), METHOCEL® J (USP type 1828),METHOCEL® K (USP type 2201), and METHOCEL® 310 Series, products of TheDow Chemical Company, Midland, Mich., USA. The average degree ofmethoxyl substitution in these products can range from about 1.3 toabout 1.9 including all values and ranges therebetween (of the threepositions on each unit of the cellulose polymer that are available forsubstitution) while the average degree of hydroxypropyl substitution perunit expressed in molar terms can range from about 0.13 to about 0.82including all values and ranges therebetween. The dosage form cancomprise the different HPMC grades having different viscosities. Thesize of a HPMC polymer is expressed not as molecular weight but insteadin terms of its viscosity as about a 2% solution by weight in water.Different HPMC grades can be combined to achieve the desired viscositycharacteristics. For example, the at least one pharmaceuticallyacceptable polymer can comprise two HPMC polymers such as for exampleMETHOCEL® K3 LV (which has a viscosity of about 3 cps) and METHOCEL®K100M CR (which has a viscosity of about 100,000 cps). In addition, thepolymer can comprise two hydroxypropylcellulose forms such as KLUCEL® LFand KLUCEL® EF. In addition, the at least one polymer can comprise amixture of a KLUCEL® and a METHOCEL®.

In at least one embodiment the controlled release matrix dosage formcomprises a polyethylene oxide (PEO). PEO is a linear polymer ofunsubstituted ethylene oxide. In certain embodiments poly(ethyleneoxide) polymers having viscosity-average molecular weights of about100,000 Daltons and higher are used. Non-limiting examples ofpoly(ethylene oxide)s that are commercially available include: POLYOX®NF, grade WSR Coagulant, molecular weight 5 million; POLYOX® grade WSR301, molecular weight 4 million; POLYOX® grade WSR 303, molecular weight7 million; POLYOX® grade WSR N-60K, molecular weight 2 million; andmixtures thereof. These particular polymers are products of Dow ChemicalCompany, Midland, Mich., USA. Other examples of polyethylene oxidesexist and can likewise be used. The required molecular weight for thePEO can be obtained by mixing PEO of differing molecular weights thatare available commercially.

In at least one embodiment of the controlled release matrix dosage form,PEO and HPMC are combined within the same controlled release matrix. Incertain embodiments, the poly(ethylene oxide)s have molecular weightsranging from about 2,000,000 to about 10,000,000 Da including all valuesand ranges therebetween. For example, in at least one embodiment thepolyethylene oxides have molecular weights ranging from about 4,000,000to about 7,000,000 Da. In certain embodiments the HPMC polymers have aviscosity within the range of about 4,000 centipoises to about 200,000centipoises. For example, in at least one embodiment the HPMC polymershave a viscosity of from about 50,000 centipoises to about 200,000centipoises, and in other embodiments from about 80,000 centipoises toabout 120,000 centipoises. The relative amounts of PEO and HPMC withinthe controlled release matrix can vary within the scope of theinvention. In at least one embodiment the PEO:HPMC weight ratio is fromabout 1:3 to about 3:1 including all values and ranges therebetween. Forexample, in certain embodiments the PEO:HPMC weight ratio is from about1:2 to about 2:1. As for the total amount of polymer relative to theentire matrix, this can vary as well and can depend on the desired drugloading. In at least one embodiment the total amount of polymer in thematrix can constitute from about 15% to about 90% by weight of thematrix dosage form including all values and ranges therebetween. Forexample, in certain embodiments the total amount of polymer in thematrix is from about 20% to about 75%, in other embodiments from about30% to about 60%, and in still other embodiments from about 10% to about20% by weight of the matrix dosage form.

In at least one embodiment of the invention the controlled releasematrix dosage form comprises a hydrophobic polymer such asethylcellulose. The viscosity of ethylcellulose can be selected in orderto influence of rate the drug release. In certain embodiments theethylcellulose has a viscosity from about 7 to about 100 cP includingall values and ranges therebetween (when measured as a 5% solution at25° C. in an Ubbelohde viscometer, using a 80:20 toluene:ethanolsolvent). In certain embodiments the hydrophobic polymer can constitutefrom about 10% to about 90% by weight of the matrix dosage formincluding all values and ranges therebetween. For example, in at leastone embodiment the hydrophobic polymer constitutes from about 20% toabout 75%, and in other embodiments from about 30% to about 60% byweight of the matrix dosage form.

In at least one embodiment of the invention the controlled releasematrix dosage form comprises at least one binder. In certain embodimentsthe binder is water-insoluble. Examples of binders include hydrogenatedvegetable oil, castor oil, paraffin, higher aliphatic alcohols, higheraliphatic acids, long chain fatty acids, fatty acid esters, wax-likematerials such as fatty alcohols, fatty acid esters, fatty acidglycerides, hydrogenated fats, hydrocarbons, normal waxes, stearic acid,stearyl alcohol, hydrophobic and hydrophilic polymers having hydrocarbonbackbones, and mixtures thereof. Non-limiting examples of water-solublepolymer binders include modified starch, gelatin, polyvinylpyrrolidone,cellulose derivatives (such as for example hydroxypropyl methylcellulose(HPMC) and hydroxypropyl cellulose (HPC)), polyvinyl alcohol andmixtures thereof. In at least one embodiment, the binder can be presentin an amount of from about 0.1% to about 20% by weight of the matrixdosage form including all values and rangs therebetween. For example, incertain embodiments the binder is present in an amount of from about0.5% to about 15%, and in other embodiments from about 2% to about 10%by weight of the matrix dosage form.

In at least one embodiment of the invention the controlled releasematrix dosage form comprises at least one lubricant. Non-limitingexamples of lubricants include stearic acid, hydrogenated vegetable oils(such as hydrogenated cottonseed oil (Sterotex®), hydrogenated soybeanoil (STEROTEX® HM) and hydrogenated soybean oil & castor wax (STEROTEX®K)) stearyl alcohol, leucine, polyethylene glycol (MW 1450, suitably4000, and higher), magnesium stearate, glyceryl monostearate, stearicacid, glycerylbehenate, polyethylene glycol, ethylene oxide polymers(e.g. CARBOWAX®), sodium lauryl sulfate, magnesium lauryl sulfate,sodium oleate, sodium stearyl fumarate, DL-leucine, colloidal silica,and mixtures thereof. The lubricant can be present in an amount of fromabout 0 to about 4% by weight of the compressed uncoated matrixincluding all values and ranges therebetween. For example, in certainembodiments the lubricant is present in an amount of from about 0% toabout 2.5% by weight of the compressed, uncoated matrix.

In at least one embodiment of the invention the controlled releasematrix dosage form comprises a plasticizer. Non-limiting examples ofplasticizers include dibutyl sebacate, diethyl phthalate, triethylcitrate, tributyl citrate, triacetin, citric acid esters such astriethyl citrate NF XVI, tributyl citrate, dibutyl phthalate,1,2-propylene glycol, polyethylene glycols, propylene glycol, diethylphthalate, castor oil, acetylated monoglycerides, phthalate esters, andmixtures thereof. In at least one embodiment, the plasticizer can bepresent in an amount of from about 1% to about 70% by weight of thecontrolled release polymer in the matrix dosage form including allvalues and ranges therebetween. For example, in certain embodiments theplasticizer is present in an amount of from about 5% to about 50%, andin other embodiments from about 10% to about 40% by weight of thecontrolled release polymer in the matrix dosage form.

In at least one embodiment of the invention the controlled releasematrix dosage form comprises at least one diluent, non-limiting examplesof which include dicalcium phosphate, calcium sulfate, lactose orsucrose or other disaccharides, cellulose, cellulose derivatives,kaolin, mannitol, dry starch, glucose or other monosaccharides, dextrinor other polysaccharides, sorbitol, inositol, sucralfate, calciumhydroxyl-apatite, calcium phosphates, fatty acid salts such as magnesiumstearate, and mixtures thereof. In certain embodiments the diluent canbe added in an amount so that the combination of the diluent and theactive substance comprises up to about 60%, and in other embodiments upto about 50%, by weight of the composition.

In at least one embodiment of the invention the controlled releasematrix dosage form comprises a solubilizer. The solubilizer can act toincrease the instantaneous solubility of the bupropion salt. Thesolubilizer can be selected from hydrophilic surfactants or lipophilicsurfactants or mixtures thereof. The surfactants can be anionic,nonionic, cationic, and zwitterionic surfactants. The hydrophilicnon-ionic surfactants can be selected from the group comprised of, butnot limited to: polyethylene glycol sorbitan fatty acid esters andhydrophilic transesterification products of a polyol with at least onemember of the group from triglycerides, vegetable oils, and hydrogenatedvegetable oils such as glycerol, ethylene glycol, polyethylene glycol,sorbitol, propylene glycol, pentaerythritol, or a saccharide,d-ce-tocopheryl polyethylene glycol 1000 succinate. The ionicsurfactants can be selected from the group comprised of, but not limitedto: alkylammonium salts; fusidic acid salts; fatty acid derivatives ofamino acids, oligopeptides, and polypeptides; glyceride derivatives ofamino acids, oligopeptides, and polypeptides; lecithins and hydrogenatedlecithins; lysolecithins and hydrogenated lysolecithins; phospholipidsand derivatives thereof; lysophospholipids and derivatives thereof;carnitine fatty acid ester salts; salts of alkylsulfates ; fatty acidsalts; sodium docusate; acyl lactylates; mono- and di-acetylatedtartaric acid esters of mono- and di-glycerides; succinylated mono- anddi-glycerides; citric acid esters of mono- and di-glycerides; andmixtures thereof. The lipophilic surfactants can be selected from thegroup comprised of, but not limited to: fatty alcohols; glycerol fattyacid esters; acetylated glycerol fatty acid esters; lower alcohol fattyacids esters; propylene glycol fatty acid esters; sorbitan fatty acidesters; polyethylene glycol sorbitan fatty acid esters; sterols andsterol derivatives; polyoxyethylated sterols and sterol derivatives;polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lacticacid derivatives of mono- and di-glycerides; hydrophobictransesterification products of a polyol with at least one member of thegroup from glycerides, vegetable oils, hydrogenated vegetable oils,fatty acids and sterols; oil-soluble vitamins/vitamin derivatives; PEGsorbitan fatty acid esters, PEG glycerol fatty acid esters,polyglycerized fatty acid, polyoxyethylene-polyoxypropylene blockcopolymers, sorbitan fatty acid esters; and mixtures thereof. In atleast one embodiment the solubilizer can be selected from:PEG-20-glyceryl stearate (e.g. CAPMUL® by Abitec), PEG-40 hydrogenatedcastor oil (e.g. CREMOPHOR RH 40® by BASF), PEG 6 corn oil (e.g.LABRAFIL® by Gattefosse), lauryl macrogol-32 glyceride (e.g.GELUCIRE44/14® by Gattefosse) stearoyl macrogol glyceride (e.g.GELUCIRE50/138 by Gattefosse), polyglyceryl-10 mono dioleate (e.g.CAPROL® PEG860 by Abitec), propylene glycol oleate (e.g. LUTROL® byBASF), Propylene glycol dioctanoate (e.g. CAPTEX® by Abitec), Propyleneglycol caprylate/caprate (e.g. LABRAFAC® by Gattefosse), Glycerylmonooleate (e.g. PECEOL® by Gattefrosse), Glycerol monolinoleate (e.g.MAISINE® by Gattefrosse), Glycerol monostearate (e.g. CAPMUL® byAbitec), PEG-20 sorbitan monolaurate (e.g. TWEEN20® by ICD, PEG-4 laurylether (e.g. BRIJ308 by ICI), Sucrose distearate (e.g. SUCROESTER7® byGattefosse), Sucrose monopalmitate (e.g. SUCROESTER15® by Gattefosse),polyoxyethylene-polyoxypropylene block copolymer (e.g. LUTROL® seriesBASF), polyethylene glycol 660 hydroxystearate, (e.g. SOLUTOL® by BASF),Sodium lauryl sulfate, Sodium dodecyl sulphate, Dioctyl suphosuccinate,L-hydroxypropyl cellulose, hydroxylethylcellulose,hydroxylpropylcellulose, Propylene glycol alginate, sodium taurocholate,sodium glycocholate, sodium deoxycholate, betains, polyethylene glycol(e.g. CARBOWAX® by DOW), d-a-tocopheryl polyethylene glycol 1000succinate, (Vitamin E TPGS® by Eastman), and mixtures thereof. In atleast one other embodiment the solubilizer can be selected from PEG-40hydrogenated castor oil (e.g. CREMOPHOR RH 40® by BASF), laurylmacrogol-32 glyceride (e.g. GELUCIRE44/14® by Gattefosse) stearoylmacrogol glyceride (e.g. GELUCIRE 50/13® by Gattefosse), PEG-20 sorbitanmonolaurate (e.g. TWEEN 20® by ICD, PEG-4 lauryl ether (e.g. BRIJ308 byICD, polyoxyethylene-polyoxypropylene block copolymer (e.g. LUTROL®series BASF), Sodium lauryl sulphate, Sodium dodecyl sulphate,polyethylene glycol (e.g. CARBOWAX® by DOW), and mixtures thereof.

In at least one embodiment of the invention the controlled releasematrix dosage form comprises a swelling enhancer. Swelling enhancers aremembers of a category of excipients that swell rapidly to a large extentresulting in an increase in the size of the tablet. At lowerconcentrations, these excipients can be used as superdisintegrants;however at concentrations above 5 w/w these agents can function asswelling enhancers and help increase the size of the matrix dosage form.According to certain embodiments of the matrix dosage forms of theinvention, examples of swelling enhancers include but are not limitedto: low--substituted hydroxypropyl cellulose, microcrystallinecellulose, cross-linked sodium or calcium carboxymethyl cellulose,cellulose fiber, cross-linked polyvinyl pyrrolidone, cross-linkedpolyacrylic acid, cross-linked Amberlite resin, alginates, colloidalmagnesium-aluminum silicate, corn starch granules, rice starch granules,potato starch granules, pregelatinised starch, sodium carboxymethylstarch and mixtures thereof. In at least one embodiment of the matrixdosage forms, the swelling enhancer is cross-linked polyvinylpyrrolidone. The content of the swelling enhancer can be from about 5%to about 90% by weight of the matrix dosage form including all valuesand ranges therebetween. For example, in certain embodiments theswelling enhancer is present in an amount of from about 10% to about70%, and in other embodiments from about 15% to about 50% by weight ofthe matrix dosage form.

In at least one embodiment of the invention the controlled releasematrix dosage form comprises additives for allowing water to penetrateinto the core of the preparation (hereinafter referred to as“hydrophilic base”). In certain embodiments, the amount of waterrequired to dissolve 1 g of the hydrophilic base is not more than about5 ml, and in other embodiments is not more than about 4 ml at thetemperature of about 20° C.±5° C. The higher the solubility of thehydrophilic base in water, the more effective is the base in allowingwater into the core of the preparation. The hydrophilic base includes,inter alia, hydrophilic polymers such as polyethylene glycol (PEG);(e.g. PEG400, PEG1500, PEG4000, PEG6000 and PEG20000, produced by NipponOils and Fats Co.) and polyvinylpyrrolidone (PVP); (e.g. PVP K30, ofBASF), sugar alcohols such as D-sorbitol, xylitol, or the like, sugarssuch as sucrose, anhydrous maltose, D-fructose, dextran (e.g. dextran40), glucose or the like, surfactants such aspolyoxyethylene-hydrogenated castor oil (HCO; e.g. CREMOPHOR® RH40produced by BASF, HCO-40 and HCO-60 produced by Nikko Chemicals Co.),polyoxyethylene-polyoxypropylene glycol (e.g. Pluronic® F68 produced byAsahi Denka Kogyo K.K.), polyoxyethylene-sorbitan high molecular fattyacid ester (TWEEN®; e.g. TWEEN® 80 produced by Kanto Kagaku K.K.), orthe like; salts such as sodium chloride, magnesium chloride., or thelike; organic acids such as citric acid, tartaric acid., or the like;amino acids such as glycine, .β-alanine, lysine hydrochloride, or thelike; and amino sugars such as meglumine. In at least one embodiment thehydrophilic base is PEG6000, PVP, D-sorbitol, or mixtures thereof.

In another embodiment of the invention the controlled release matrixdosage form comprises at least one disintegrant. Non-limiting examplesof disintegrants for use in the matrix dosage form includecroscarmellose sodium, crospovidone, alginic acid, sodium alginate,methacrylic acid DVB, cross-linked PVP, microcrystalline cellulose,polacrilin potassium, sodium starch glycolate, starch, pregelatinizedstarch and mixtures thereof. In at least one embodiment the disintegrantis selected from cross-linked polyvinylpyrrolidone (e.g. KOLLIDON® CL),cross-linked sodium carboxymethylcellulose (e.g. AC-DI-SOL™), starch orstarch derivatives such as sodium starch glycolate (e.g. EXPLOTAB®), orcombinations with starch (e.g. PRIMOJEL™), swellable ion-exchangeresins, such as AMBERLITE™ IRP 88, formaldehyde-casein (e.g. ESMASPRENG™), and mixtures thereof. In at least one embodiment thedisintegrant is sodium starch glycolate. The disintegrant can be presentin certain embodiments in an amount of from about 0% to about 20% of thetotal weight of the matrix including all values and ranges therebetween.

The controlled release matrices of the present invention can furthercontain one or more pharmaceutically acceptable excipients such asgranulating aids or agents, colorants, flavorants, pH adjusters,anti-adherents, glidants and like excipients conventionally used inpharmaceutical compositions.

In at least one embodiment of the invention comprising water swellablepolymers formulated into the matrix, the release kinetics of thebupropion hydrobromide salt from the matrix are dependent upon therelative magnitude of the rate of polymer swelling at the movingrubbery/glassy front and the rate of polymer erosion at the swollenpolymer/dissolution medium front. The release kinetics for the releaseof the bupropion hydrobromide salt from the matrix can be approximatedby the following equation:

Mt/MT=ktn

where t is time,Mt is the amount of the pharmaceutical agent which has been released attime t,MT is the total amount of the pharmaceutical agent contained in thematrix,k is a constant, andn is the release kinetics exponent

This equation is valid so long as n remains nearly constant. When n isequal to one, the release of the pharmaceutical agent from the matrixhas zero-order kinetics. The amount of pharmaceutical agent released isthen directly proportional to the time.

Where the swelling process of the polymer chosen for the excipient isthe primary process controlling the drug release (compared to erosion ofthe swollen polymer), non-zero order release kinetics can result.Generally, these release kinetics dictate a value of n approaching 0.5,leading to square-root Fickian-type release kinetics.

In at least one embodiment of the invention, polymers are selected forinclusion into the formulation to achieve zero order kinetics. Therelease kinetics of the matrix can also be dictated by thepharmaceutical agent itself. A drug which is highly soluble (e.g.bupropion) can tend to be released faster than drugs which have lowsolubility. Where a drug has high solubility, polymer swelling anderosion takes place rapidly to maintain zero order release kinetics. Ifthe swelling and erosion take place too slowly, the swelling process ofthe polymer is the primary process controlling the drug release (sincethe drug will diffuse from the swollen polymer before the polymererodes). In this situation, non-zero order release kinetics can result.As a result, the administration of a highly soluble pharmaceutical agentrequires a relatively rapidly swelling and eroding excipient. To usesuch a material to produce a matrix which will last for 24 hours canrequire a large matrix. To overcome this difficulty, a doughnut-shapedmatrix with a hole though the middle can be used with a less rapidlyswelling and eroding polymer. With such a matrix, the surface area ofthe matrix increases as the matrix erodes. This exposes more polymer,resulting in more polymer swelling and erosion as the matrix shrinks insize. This type of matrix can also be used with very highly solublepharmaceutical agents to maintain zero order release kinetics.

In at least one other embodiment of the invention, zero order drugrelease kinetics can be achieved by controlling the surface area of thematrix dosage form that is exposed to erosion. When water is allowed todiffuse into a polymer matrix composition zero order release is obtainedwhen the release rate is governed or controlled by erosion of a constantsurface area per time unit. In order to ensure that the erosion of thepolymer matrix composition is the predominant release mechanism, it ishelpful to provide a polymer matrix composition which has propertiesthat ensures that the diffusion rate of water into the polymer matrixcomposition substantially corresponds to the dissolution rate of thepolymer matrix composition into the aqueous medium. Thus, by adjustingthe nature and amount of constituents in the polymer matrix compositiona zero order release mechanism can be achieved. The compositionsemployed are coated in such a manner that at least one surface isexposed to the aqueous medium and this surface has a substantiallyconstant or controlled surface area during erosion. In the presentcontext controlled surface area relates to a predetermined surface areatypically predicted from the shape of the coat of the unit dosagesystem. It may have a simple uniform cylindrical shape or thecylindrical form can have one or more tapered ends in order to decrease(or increase) the initial release period.

Accordingly, these embodiments provide a method for controlling therelease of a bupropion salt into an aqueous medium by erosion of atleast one surface of a pharmaceutical composition comprising

(i) a matrix composition comprising (a) a polymer or a mixture ofpolymers, (b) a bupropion hydrobromide salt and, optionally, (c) one ormore pharmaceutically acceptable excipients, and(ii) a coating having at least one opening exposing at the one surfaceof said matrix, the coating comprising: (a) a first cellulose derivativewhich has thermoplastic properties and which is substantially insolublein the aqueous medium in which the composition is to be used, and atleast one of (b) a second cellulose derivative which is soluble ordispersible in water, (c) optionally a plasticizer, or (d) a filler, themethod comprising adjusting the concentration and/or the nature of theingredients making up the matrix composition in such a manner that thediffusion rate of the aqueous medium into the matrix compositioncorresponds to 100%±30% such as, for example 100%±25%, 100%±20%,100%±15% or 100%±10%, or 100% of the dissolution rate of the matrixcomposition so as to obtain a zero order release of at least about 60%w/w such as, for example at least about 65% w/w, at least about 70% w/w,at least about 75% w/w, at least about 80% w/w, at least about 85% w/w,at least about 90% w/w, at least about 95% w/w or at least about 97% toabout 98% w/w of the bupropion hydrobromide salt from the pharmaceuticalcomposition when subject to an in-vitro dissolution test.

In at least one other embodiment of the invention, zero order drugrelease is approached through the use of: (a) a deposit-core comprisingthe bupropion hydrobromide salt and having defined geometric form, (b) asupport-platform applied to said deposit-core, and is characterized inthat the deposit-core contains, mixed with the bupropion hydrobromidesalt, a polymeric material having a high degree of swelling on contactwith water or aqueous liquids, a gellable polymeric material, saidpolymeric materials being replaceable by a single polymeric materialhaving both swelling and gelling properties, and other adjuvants able toprovide the mixture with suitable characteristics for its compressionand for its intake of water, said support-platform comprising apolymeric material insoluble in aqueous liquids and partially coatingsaid deposit-core.

These and further characteristics and advantages of the system accordingto certain embodiments of the matrix dosage form will be more apparentfrom the description of embodiments of the invention given hereinafterby way of non-limiting example. The deposit-core can generally beobtained by compressing the mixture containing the bupropionhydrobromide salt to a pressure of from about 1000 to about 4000 kg/cm2including all values and ranges therebetween, to thus assume a definedgeometric form. Polymeric materials having a high degree of swelling cangenerally be cross-linked insoluble polymers, whereas gellable polymericmaterials are soluble, and can control the intake of water.

The coating platform comprises a polymeric material insoluble in waterand optionally insoluble in biodegradable biological liquids, and ableto maintain its impermeability characteristics at least until thecomplete transfer of the bupropion hydrobromide salt contained in thedeposit-core. It is applied to a part of the external deposit-coresurface chosen such as to suitably direct and quantitatively regulatethe release of the bupropion hydrobromide salt. In this respect, as thesupport-platform is impermeable to water, the polymeric material of thedeposit-core in certain embodiments can swell only in that portion ofthe deposit not coated with the platform.

The support-platform can be obtained by compressing prechosen polymericmaterials onto the deposit-core, by immersing the deposit-core in asolution of said polymeric materials in normal organic solvents, or byspraying said solutions. Polymeric materials usable for preparing thesupport-platform can be chosen from the class comprising acrylates,celluloses and derivatives such as ethylcellulose, celluloseacetate-propionate, polyethylenes and methacrylates and copolymers ofacrylic acid, polyvinylalcohols and mixtures thereof. This platform canhave a thickness of from about 2 mm (for example, if applied bycompression) to about 10 microns (for example, if applied by spraying orimmersion) including all values and ranges therebetween, and comprisesfrom about 10% to about 90% of the total surface of the system includingall values and ranges therebetween.

A factor in controlling the release of the bupropion hydrobromide saltis the intensity and duration of the swelling force developed by theswellable polymeric materials contained in the deposit-core on contactwith aqueous fluids. In this respect, the energy for activating,executing and regulating the release of the bupropion hydrobromide saltcan be determined by the swelling force developed in the deposit-corewhen this comes into contact with water or with biological liquids. Saidforce has an intensity and duration which can vary in relation to thetype and quantity of the polymeric materials used in formulating thedeposit, and it lies between limits having a maximum value which occursin the case of a deposit mainly containing the swellable polymer, and aminimum value which occurs in the case of a deposit mainly containingthe gellable polymer. Said swellable polymer can be present in an amountof from about 5% to about 80% by weight including all values and rangestherebetween, and said gellable polymer present in an amount of fromabout 10% to about 90% by weight including all values and rangestherebetween, with respect to the mixture forming the deposit-core.

A further control factor is the geometry of the support-platform, whichlimits the swelling of the deposit and directs the emission of materialfrom it. Within the scope of these embodiments it is possible toconceive many systems for the controlled release of bupropionhydrobromide, which base their operation on the swelling force anddiffer from each other by the type of support-platform used.

In at least one other embodiment of the invention designed to achievezero order release of the bupropion hydrobromide salt, the kinetics ofdrug release from a controlled release matrix is governed by acombination of different polymers with different swellingcharacteristics. More specifically, the bupropion hydrobromide salt isfirst granulated with or encapsulated in a less swellable polymer, suchas a gum, to form a granule. This granule is disposed in a matrix of amore swellable, erodible polymer. The more swellable erodible polymerhas a diffusion rate coefficient which is greater than the diffusionrate coefficient of the relatively less swellable polymer. Averaged overthe entire period of drug release, the diffusion rate for the moreswellable polymer is greater than the diffusion rate for the lessswellable polymer. It is this general difference in rates of diffusionbetween the first and second polymers which controls the rate of drugrelease and allows the system to approach zero order drug delivery overthe drug release period. In at least one embodiment, pectin and HPMC arepresent as the more swellable polymers in ratios of from about 2:7 toabout 4:5 including all values and ranges therebetween, and gelatin ispresent as the less swellable polymer.

In at least one other embodiment of the invention there is provided acontrolled release matrix composition comprising bupropion hydrobromideincorporated within a homogeneous matrix including effective amounts ofat least two polymers having opposing wettability characteristics,wherein at least one polymer is selected which demonstrates a strongertendency towards hydrophobicity and the other polymer(s) is selectedwhich demonstrates a stronger tendency towards hydrophilicity. In atleast one embodiment the polymer demonstrating a stronger tendencytowards hydrophobicity is ethylcellulose (EC) whereas the polymerdemonstrating a stronger tendency towards hydrophilicity ishydroxyethylcellulose (HEC) and/or hydroxypropyl methylcellulose (HPMC).The composition and device of the present invention can be provided as amatrix and can be optionally encased in a coating material whichprevents the burst and/or food effect associated with orally ingestedmedicaments and imparts gastrointestinal “stealth” characteristics. Inaccordance with at least one embodiment is a method for preparing adevice for the controlled release of the bupropion hydrobromide salt,the method comprising blending bupropion hydrobromide with from about 5%to about 25% by weight of hydrophilic polymer including all values andranges therebetween, and from about 1% to about 25% by weight ofhydrophobic polymer including all values and ranges therebetween, addingsuitable pharmaceutical excipients, surface active agents andlubricants, granulating the mixture with solvents such as isopropylalcohol, drying the granular mixture, milling the dried mixture, addingfrom about 5% to about 70% by weight of ethylcellulose including allvalues and ranges therebetween, adding a lubricant and optionally aglidant and compressing the granules into matrices. The matrices areoptionally encased in a gastrointestinal encasement or apharmaceutically acceptable film coat.

In another embodiment of the present invention, a swellable matrixdosage form is provided in which the bupropion hydrobromide salt isdispersed in a polymeric matrix that is water-swellable rather thanmerely hydrophilic, that has an erosion rate that is substantiallyslower than its swelling rate, and that releases the bupropionhydrobromide salt primarily by diffusion. The rate of diffusion of thebupropion hydrobromide salt out of the swellable matrix can be slowed byincreasing the drug particle size, by the choice of polymer used in thematrix, and/or by the choice of molecular weight of the polymer. Theswellable matrix is comprised of a relatively high molecular weightpolymer that swells upon ingestion. In at least one embodiment theswellable matrix swells upon ingestion to a size that is at least twiceits unswelled volume, and that promotes gastric retention during the fedmode. Upon swelling, the swellable matrix can also convert over aprolonged period of time from a glassy polymer to a polymer that isrubbery in consistency, or from a crystalline polymer to a rubbery one.The penetrating fluid then causes release of the bupropion hydrobromidesalt in a gradual and prolonged manner by the process of solutiondiffusion, i.e., dissolution of the bupropion hydrobromide salt in thepenetrating fluid and diffusion of the dissolved bupropion hydrobromidesalt back out of the swellable matrix. The swellable matrix itself issolid prior to administration and, once administered, remainsundissolved in (i.e., is not eroded by) the gastric fluid for a periodof time sufficient to permit the majority of the bupropion hydrobromidesalt to be released by the solution diffusion process during the fedmode. The rate-limiting factor in the release of the bupropionhydrobromide salt from the swellable matrix is therefore controlleddiffusion of the bupropion hydrobromide salt from the swellable matrixrather than erosion, dissolving or chemical decomposition of theswellable matrix.

As such, the swelling of the polymeric matrix can achieve at least thefollowing objectives:

(i) renders the matrix sufficiently large to cause retention in thestomach during the fed mode;(ii) localizes the release of the drug to the stomach and smallintestine so that the drug will have its full effect without colonicdegradation, inactivation, or loss of bioavailability; (iii) retards therate of diffusion of the drug long enough to provide multi-hour,controlled delivery of the drug into the stomach.

The bupropion hydrobromide salt in the swellable matrix can be presentin an effective amount of from about 0.1% to about 99% by weight of thematrix including all values and ranges therebetween. For example, incertain embodiments bupropion hydrobromide is present in the swellablematrix in an amount of from about 0.1% to about 90%, in otherembodiments from about 5% to about 90%, in still other embodiments fromabout 10% to about 80%, and in even still other embodiments from about25% to about 80% by weight of the swellable matrix.

The water-swellable polymer forming the swellable matrix in accordancewith these embodiments of the present invention can be any polymer thatis non-toxic, that swells in a dimensionally unrestricted manner uponimbibition of water, and that provides for a modified release of thebupropion hydrobromide salt. Non-limiting examples of polymers suitablefor use in the swellable matrix include cellulose polymers and theirderivatives, such as for example, hydroxyethylcellulose,hydroxypropylcellulose, carboxymethylcellulose, and microcrystallinecellulose, polysaccharides and their derivatives, polyalkylene oxides,polyethylene glycols, chitosan, poly(vinyl alcohol), xanthan gum, maleicanhydride copolymers, poly(vinyl pyrrolidone), starch and starch-basedpolymers, poly (2-ethyl-2-oxazoline), poly(ethyleneimine), polyurethanehydrogels, and crosslinked polyacrylic acids and their derivatives, andmixtures thereof. Further examples include copolymers of the polymerslisted in the preceding sentence, including block copolymers and graftedpolymers. Specific examples of copolymers include PLURONIC® andTECTONIC®, which are polyethylene oxide-polypropylene oxide blockcopolymers.

The terms “cellulose” and “cellulosic”, as used within this sectionregarding the swellable matrix embodiments of the present invention, candenote a linear polymer of anhydroglucose. Non-limiting examples ofcellulosic polymers include alkyl-substituted cellulosic polymers thatultimately dissolve in the gastrointestinal (GI) tract in a predictablydelayed manner. In certain embodiments the alkyl-substituted cellulosederivatives are those substituted with alkyl groups of 1 to 3 carbonatoms each. Non-limiting examples include methylcellulose,hydroxymethyl-cellulose, hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, carboxymethylcellulose, and mixturesthereof. In terms of their viscosities, one class of alkyl-substitutedcelluloses includes those whose viscosity is within the range of about100 to about 110,000 centipoises as a 2% aqueous solution at 20° C.Another class includes those whose viscosity is within the range ofabout 1,000 to about 4,000 centipoises as a 1% aqueous solution at 20°C. In certain embodiments the alkyl-substituted celluloses arehydroxyethylcellulose and hydroxypropylmethylcellulose. In at least oneembodiment the hydroxyethylcellulose is NATRASOL® 250HX NF.

Polyalkylene oxides that can be used in certain embodiments of theswellable matrices include those having the properties described abovefor alkyl-substituted cellulose polymers. In at least one embodiment thepolyalkylene oxide is poly(ethylene oxide), which term is used herein todenote a linear polymer of unsubstituted ethylene oxide. In at least oneembodiment the poly(ethylene oxide) polymers have molecular weights ofabout 4,000,000 and higher. For example, in certain embodiment thepoly(ethylene oxide) polymers have molecular weights within the range ofabout 4,500,000 to about 10,000,000 including all values and rangestherebetween, and in other embodiments have molecular weights within therange of about 5,000,000 to about 8,000,000. In certain embodiments thepoly(ethylene oxide)s are those with a weight-average molecular weightwithin the range of about 1×105 to about 1×107, and in other embodimentswithin the range of about 9×105 to about 8×106. Poly(ethylene oxide)sare often characterized by their viscosity in solution. For example, incertain embodiments the poly(ethylene oxide)s have a viscosity range ofabout 50 to about 2,000,000 centipoises for a 2% aqueous solution at 20°C. In at least one embodiment the poly(ethylene oxide) is one or more ofPOLYOX® NF, grade WSR Coagulant, molecular weight 5 million, and gradeWSR 303, molecular weight 7 million. Mixtures thereof are operable.

Polysaccharide gums, both natural and modified (semi-synthetic) can beused in the swellable matrix embodiments of the present invention.Non-limiting examples include dextran, xanthan gum, gellan gum, welangum, rhamsan gum, and mixtures thereof. In at least one embodiment thepolysaccharide gum is xanthan gum.

Crosslinked polyacrylic acids that can be used in the swellable matricesof the present invention include those whose properties are the same asthose described above for alkyl-substituted cellulose and polyalkyleneoxide polymers. In certain embodiments the crosslinked polyacrylic acidsare those with a viscosity ranging from about 4,000 to about 40,000centipoises for a 1% aqueous solution at 25° C. Non-limiting examples ofsuitable crosslinked polyacrylic acids include CARBOPOL® NF grades 971P,974P and 934P. Further examples of suitable crosslinked polyacrylicacids include polymers known as WATER LOCK®, which arestarch/acrylates/acrylamide copolymers.

The hydrophilicity and water swellability of these polymers can causethe drug-containing swellable matrices to swell in size in the gastriccavity due to ingress of water in order to achieve a size that can beretained in the stomach when introduced during the fed mode. Thesequalities also cause the swellable matrices to become slippery, whichprovides resistance to peristalsis and further promotes their retentionin the stomach. The release rate of drug from the swellable matrix isprimarily dependent upon the rate of water imbibition and the rate atwhich the drug dissolves and diffuses from the swollen polymer, which inturn is related to the drug concentration in the swellable matrix. Also,because these polymers dissolve very slowly in gastric fluid, theswellable matrix maintains its physical integrity over at least asubstantial period of time, for example in many cases at least about 90%and in certain embodiments over about 100% of the dosing period. Theparticles will then slowly dissolve or decompose. Complete dissolutionor decomposition may not occur until about 24 hours or more after theintended dosing period ceases, although in most cases, completedissolution or decomposition will occur within about 10 to about 24hours after the dosing period.

The amount of polymer relative to the drug can vary, depending on thedrug release rate desired and on the polymer, its molecular weight, andexcipients that may be present in the formulation. The amount of polymerwill typically be sufficient to retain at least about 40% of the drugwithin the swellable matrix about one hour after ingestion (or immersionin the gastric fluid). In certain embodiments, the amount of polymer issuch that at least about 50% of the drug remains in the matrix about onehour after ingestion; in other embodiments at least about 60%, and instill other embodiments at least about 80% of the drug remains in theswellable matrix about one hour after ingestion. In certain embodimentsthe drug will be substantially all released from the swellable matrixwithin about 10 hours; and in other embodiments within about 8 hours,after ingestion, and the polymeric matrix will remain substantiallyintact until all of the drug is released. In other embodiments theamount of polymer will be such that after about 2 hours no more thanabout 40% is released; after about 4 hours from about 40% to about 75%is released; after about 8 hours at least about 75% is released, andafter about 16 hours at least about 85% is released. The term“substantially intact” is used herein to denote a polymeric matrix inwhich the polymer portion substantially retains its size and shapewithout deterioration due to becoming solubilized in the gastric fluidor due to breakage into fragments or small particles.

In other exemplary embodiments the swellable matrix after about 2 hourswill release no more than about 40% of the bupropion hydrobromide, afterabout 4 hours from about 40% to about 75%, after about 8 hours at leastabout 75%, and after about 16 hours at least about 85% of the bupropionhydrobromide.

The water-swellable polymers of the swellable matrices can be usedindividually or in combination. Certain combinations will often providea more controlled release of the drug than their components when usedindividually. Examples include cellulose-based polymers combined withgums, such as hydroxyethyl cellulose or hydroxypropyl cellulose combinedwith xanthan gum. Another example is poly(ethylene oxide) combined withxanthan gum.

The benefits of certain embodiments of this invention can be achievedover a wide range of drug loadings and polymer levels, with the weightratio of drug to polymer ranging in general from about 0.01:99.99 toabout 80:20, including all values and ranges therebetween. For example,in certain embodiments the drug loadings (expressed in terms of theweight percent of drug relative to total of drug and polymer) are withinthe range of about 15% to about 80% including all values and rangestherebetween; in other embodiments within the range of about 30% toabout 80% including all values and ranges therebetween; and in stillother embodiments within the range of about 30% to about 70% includingall values and ranges therebetween. In at least one embodiment the drugloading is within the range of about 0.01% to about 80% including allvalues and ranges therebetween, and in at least one other embodimentfrom about 15% to about 80% including all values and rangestherebetween. In at least one embodiment the weight ratio of bupropionhydrobromide to polymer in the swellable matrix is from about 15:85 toabout 80:20 including all values and ranges therebetween.

The formulations of the swellable matrices of the present invention canassume the form of microparticles, tablets, or microparticles retainedin capsules. In at least one embodiment the formulation comprisesmicroparticles consolidated into a packed mass for ingestion, eventhough the packed mass will separate into individual particles afteringestion. Conventional methods can be used for consolidating themicroparticles in this manner. For example, the microparticles can beplaced in gelatin capsules known in the art as “hard-filled” capsulesand “soft-elastic” capsules. The compositions of these capsules andprocedures for filling them are known among those skilled in drugformulations and manufacture. The encapsulating material should behighly soluble so that the particles are freed and rapidly dispersed inthe stomach after the capsule is ingested.

In certain embodiments of the swellable matrices of the presentinvention, the formulation contains an additional amount of bupropionhydrobromide salt or other drug applied as a quickly dissolving coatingon the outside of the microparticle or tablet. This coating is referredto as a “loading dose” and it is included for immediate release into therecipient's bloodstream upon ingestion of the formulation without firstundergoing the diffusion process that the remainder of the drug in theformulation must pass before it is released. The “loading dose” can behigh enough to quickly raise the blood concentration of the drug but nothigh enough to produce the transient overdosing that is characteristicof immediate release dosage forms that are not formulated in accordancewith this invention.

In at least one embodiment of the swellable matrices of the presentinvention, the dosage form is a size 0 gelatin capsule containing eithertwo or three pellets of drug-impregnated polymer. For two-pelletcapsules, the pellets are cylindrically shaped, about 6.6 mm or about6.7 mm in diameter (or more generally, from about 6.5 mm to about 7 mmin diameter including all values and ranges therebetween) and about 9.5mm or about 10.25 mm in length (or more generally, from about 9 mm toabout 12 mm in length including all values and ranges therebetween). Forthree-pellet capsules, the pellets are again cylindrically shaped, about6.6 mm in diameter and about 7 mm in length. For a size 00 gelatincapsule with two pellets, the pellets are cylindrical, about 7.5 mm indiameter and about 11.25 mm in length. For a size 00 gelatin capsulewith three pellets, the pellets are cylindrical, about 7.5 mm indiameter and about 7.5 mm in length. In at least one other embodiment,the dosage form is a single, elongated tablet, with dimensions of about18 mm to about 22 mm in length including all values and rangestherebetween, from about 6.5 mm to about 10 mm in width including allvalues and ranges therebetween, and from about 5 mm to about 7.5 mm inheight including all values and ranges therebetween. In at least oneother embodiment, the dosage form is a single, elongated tablet, withdimensions of from about 18 mm to about 22 mm in length including allvalues and ranges therebetween, from about 6.5 mm to about 7.8 mm inwidth including all values and ranges therebetween, and from about 6.2mm to about 7.5 mm in height including all values and rangestherebetween. In at least one embodiment the dimensions are about 20 mmin length, about 6.7 mm in width, and about 6.4 mm in height. These aremerely examples; the shapes and sizes can be varied considerably.

In certain embodiments the bupropion hydrobromide-containing matrix canbe made according to any one of the methods described herein.

The particulate drug/polymer mixture or drug-impregnated swellablepolymer matrix of certain embodiments can be prepared by variousconventional mixing, comminution and fabrication techniques readilyapparent to those skilled in the chemistry of drug formulations.Examples of such techniques include: (1) Direct compression, usingappropriate punches and dies, such as those available from ElizabethCarbide Die Company, Inc., McKeesport, Pa., USA; the punches and diesare fitted to a suitable rotary tableting press, such as theElizabeth-Hata single-sided Hata Auto Press machine, with either 15, 18or 22 stations, and available from Elizabeth-Hata International, Inc.,North Huntington, Pa., USA; (2) Injection or compression molding usingsuitable molds fitted to a compression unit, such as those availablefrom Cincinnati Milacron, Plastics Machinery Division, Batavia, Ohio,USA.; (3) Granulation followed by compression; and (4) Extrusion in theform of a paste, into a mold or to an extrudate to be cut into lengths.

In regards to the swellable matrices of certain embodiments of thepresent invention, when microparticles are made by direct compression,the addition of lubricants can be helpful and, in certain embodiments,helpful to promote powder flow and to prevent capping of themicroparticle (breaking off of a portion of the particle) when thepressure is relieved. Non-limiting examples of suitable lubricantsinclude magnesium stearate (in a concentration of from about 0.25% toabout 3% by weight including all values and ranges therebetween, and incertain embodiments less than about 1% by weight, in the powder mix),and hydrogenated vegetable oil (in certain embodiments hydrogenated andrefined triglycerides of stearic and palmitic acids at from about 1% toabout 5% by weight including all values and ranges therebetween, forexample in at least one embodiment at about 2% by weight). Additionalexcipients can be added to enhance powder flowability and reduceadherence.

Certain embodiments of the swellable matrices of the present inventioncan find utility when administered to a subject who is in the digestivestate (also referred to as the postprandial or “fed” mode). Thepostprandial mode is distinguishable from the interdigestive (or“fasting”) mode by their distinct patterns of gastroduodenal motoractivity, which determine the gastric retention or gastric transit timeof the stomach contents.

The controlled release matrices of certain embodiments of the presentinvention can be manufactured by methods known in the art. An example ofa method of manufacturing controlled release matrices is melt-extrusionof a mixture containing the bupropion salt, hydrophobic polymer(s),hydrophilic polymer(s), and optionally a binder, plasticizer, and otherexcipient(s) as described above. Other examples of methods ofmanufacturing controlled release matrices include wet granulation, drygranulation (e.g. slugging, roller compaction), direct compression meltgranulation, and rotary granulation.

Additionally, controlled release particles which can be compressed orplaced in capsules can be produced by combining the bupropionhydrobromide salt and a hydrophobic fusible component and/or a diluent,optionally with a release modifying agent including a water solublefusible material or a particulate soluble or insoluble organic orinorganic material. Examples of potential hydrophobic fusible componentsinclude hydrophobic materials such as natural or synthetic waxes or oils(e.g., hydrogenated vegetable oil, hydrogenated castor oil,microcrystalline wax, Beeswax, carnauba wax and glyceyl monostearate).In at least one embodiment the hydrophobic fusible component has amelting point from about 35° C. to about 140° C. including all valuesand ranges therebetween. Examples of release modifying agents includepolyethylene glycol and particulate materials such as dicalciumphosphate and lactose.

In certain embodiments, controlled release matrices can be produced bymechanically working a mixture of bupropion hydrobromide salt, ahydrophobic fusible component, and optionally a release componentincluding a water soluble fusible material or a particulate soluble orinsoluble organic or inorganic material under mixing conditions thatyield aglomerates, breaking down the agglomerates to produce controlledrelease seeds having desired release properties; and optionally addingmore carrier or diluent and repeating the mixing steps until controlledrelease seeds having desired release properties are obtained. Theseparticles also can be size separated (e.g. by sieving and encapsulatedin capsules or compressed into a matrix).

The amount of the hydrophobic fusible material used in the foregoingmethods can range from about 10% to about 90% by weight including allvalues and ranges therebetween.

Mixers useful in such methods are known and include conventionalhigh-speed mixers with stainless steel interiors. For example, a mixturecan be processed until a bed temperature of about 40° C. or higher isrealized, and the mixture achieves a cohesive granular texturecomprising desired particle sizes.

As noted if the mixture contains agglomerates, they can be broken downusing conventional methods to produce a mixture of powder and particlesof the desired size which, can be size-separated using a sieve, screenor mesh of the appropriate size. This material can be returned to ahigh-speed mixer and further processed as desired until the hydrophobicfusible materials begin to soften/melt, and optionally additionalhydrophobic material can be added and mixing continued until particleshaving a desired size range are obtained. Still further, particlescontaining bupropion hydrobromide salt can be produced by meltprocessing as known in the art and combined into capsules or compressedinto matrices.

These particles can be combined with one or more excipients such asdiluents, lubricants, binding agents, flow aids, disentegrating agents,surface acting agents, water soluble materials, colorants, and the like.

In addition, the controlled release matrices can optionally be coatedwith one or more functional or non-functional coatings using well-knowncoating methods. Examples of coatings can include the XL controlledrelease coat and the EA matrix coating described herein, which canfurther control the release of the bupropion hydrobromide salt and/orother drug.

In at least one embodiment, the controlled release matrices can each becoated with at least one taste-masking coating. The taste-maskingcoating can mask the taste of the bupropion hydrobromide salt in thematrices. In at least one embodiment the taste-masking coatingformulations contain polymeric ingredients. It is contemplated thatother excipients consistent with the objects of the present inventioncan also be used in the taste-masking coating.

In at least one embodiment of the matrix dosage form, the taste-maskingcoating comprises a polymer such as ethylcellulose, which can be used asa dry polymer (such as ETHOCEL) solubilised in organic solvent prior touse, or as an aqueous dispersion. One commercially-available aqueousdispersion of ethylcellulose is AQUACOAT®. AQUACOAT® can be prepared bydissolving the ethylcellulose in a water-immiscible organic solvent andthen emulsifying the same in water in the presence of a surfactant and astabilizer. After homogenization to generate submicron droplets, theorganic solvent is evaporated under vacuum to form a pseudolatex. Theplasticizer is not incorporated in the pseudolatex during themanufacturing phase. Thus, prior to using the same as a coating, theAquacoat is intimately mixed with a suitable plasticizer prior to use.Another aqueous dispersion of ethylcellulose is commercially availableas SURELEASE®. This product can be prepared by incorporating plasticizerinto the dispersion during the manufacturing process. A hot melt of apolymer, plasticizer (e.g. dibutyl sebacate), and stabilizer (e.g. oleicacid) is prepared as a homogeneous mixture, which is then diluted withan alkaline solution to obtain an aqueous dispersion which can beapplied directly onto substrates.

In other embodiments of the matrix dosage form, polymethacrylate acrylicpolymers can be employed as taste masking polymers. In at least oneembodiment, the taste masking coating is an acrylic resin lacquer usedin the form of an aqueous dispersion, such as EUDRAGIT® or KOLLICOAT®.In further embodiments, the acrylic coating comprises a mixture of twoacrylic resin lacquers EUDRAGIT® RL and EUDRAGIT® RS, respectively.EUDRAGIT® RL and EUDRAGIT® RS are copolymers of acrylic and methacrylicesters with a low content of quaternary ammonium groups, the molar ratioof ammonium groups to the remaining neutral (meth)acrylic esters being1:20 in EUDRAGIT® RL and 1:40 in EUDRAGIT® RS. The mean molecular weightis 150,000. The code designations RL (high permeability) and RS (lowpermeability) refer to the permeability properties of these agents.EUDRAGIT® RL/RS mixtures are insoluble in water and in digestive fluids.However, coatings formed from the same are swellable and permeable inaqueous solutions and digestive fluids. EUDRAGIT® RL/RS dispersions orsolutions of the certain embodiments can be mixed together in anydesired ratio in order to ultimately obtain a taste masking coatinghaving a desirable drug dissolution profile. Controlled releaseformulations of certain embodiments can be obtained, for example, from aretardant coating derived from 100% EUDRAGIT® RL; 50% EUDRAGIT® RL with50% EUDRAGIT® RS; and 10% EUDRAGIT® RL with 90% EUDRAGIT® RS.

In other embodiments of the matrix dosage form, the taste maskingpolymer can be an acrylic polymer which is cationic in character basedon dimethylaminoethyl methacrylate and neutral methacrylic acid esters(such as EUDRAGIT® E). The hydrophobic acrylic polymer coatings of thepresent invention can further include a neutral copolymer based on poly(meth)acrylates, such as EUDRAGIT® NE. EUDRAGIT® NE 30D lacquer filmsare insoluble in water and digestive fluids, but permeable andswellable.

In other embodiments of the matrix dosage form, the taste maskingpolymer is a dispersion of poly (ethylacrylate, methyl methacrylate) 2:1(KOLLICOAT® EMM 30 D).

In other embodiments of the matrix dosage form, the taste maskingpolymer can be a polyvinyl acetate stabilized with polyvinylpyrrolidoneand sodium lauryl sulfate such as KOLLICOAT® SR30D.

Other taste masking polymers that can be used in the matrix dosage formsinclude hydroxypropylcellulose (HPC); hydroxypropylmethylcellulose(HPMC); hydroxyethylcellulose; gelatin; gelatin/acacia;gelatin/acacia/vinvylmethylether maleic anhydride;gelatin/acacia/ethylenemaleic anhydride; carboxymethyl cellulose;polyvinvylalcohol; nitrocellulose; polyvinylalcohol-polyethylene glycolgraft-copolymers; shellac; wax and mixtures thereof.

The taste-masking coatings can be applied to the matrices from one ormore organic or aqueous solvent solutions or suspensions. In at leastone embodiment of the matrix dosage forms the organic solvents that canbe used to apply the taste-masking coatings include one or more ofacetone, lower alcohols such as ethanol, isopropanol and alcohol/watermixtures, chlorinated hydrocarbons, and the like. Devices used to coatthe matrices of certain embodiments with a taste-masking coating includethose conventionally used in pharmaceutical processing, such asfluidized bed coating devices. The controlled release coatings appliedto the matrices can contain ingredients other than the cellulosicpolymers. One or more colorants, flavorants, sweeteners, can also beused in the taste-masking coating.

In some embodiments of the matrix dosage forms, a pore former can beincluded into the taste masking coat in order to influence the rate ofrelease of bupropion hydrobromide from the matrix. In other embodiments,a pore former is not included in the taste masking coat. The poreformers can be inorganic or organic, and may be particulate in natureand include materials that can be dissolved, extracted or leached fromthe coating in the environment of use. Upon exposure to fluids in theenvironment of use, the pore-formers can for example be dissolved, andchannels and pores are formed that fill with the environmental fluid.

For example, the pore-formers of certain embodiments of the matrixdosage forms can comprise one or more water-soluble hydrophilic polymersin order to modify the release characteristics of the formulation.Examples of suitable hydrophilic polymers that can be used aspore-formers include hydroxypropylmethylcellulose, cellulose ethers andprotein-derived materials of these polymers, the cellulose ethers, suchas hydroxyalkylcelluloses, carboxyalkylcelluloses and mixtures thereof.Also, synthetic water-soluble polymers can be used, examples of whichinclude polyvinylpyrrolidone, cross-linked polyvinyl-pyrrolidone,polyethylene oxide, water-soluble polydextrose, saccharides andpolysaccharides, such as pullulan, dextran, sucrose, glucose, fructose,mannitol, lactose, mannose, galactose, sorbitol and mixtures thereof. Inat least one embodiment, the hydrophilic polymer compriseshydroxypropyl-methylcellulose.

Other non-limiting examples of pore-formers that can be used in thetaste masking coat include alkali metal salts such as lithium carbonate,sodium chloride, sodium bromide, potassium chloride, potassium sulfate,potassium phosphate, sodium acetate, sodium citrate and mixturesthereof. The pore-forming solids can also be polymers which are solublein the environment of use, such as CARBOWAX™ and CARBOPOL™. In addition,the pore-formers embrace diols, polyols, polyhydric alcohols,polyalkylene glycols, polyglycols, poly(a-w)alkylenediols and mixturesthereof. Other pore-formers which can be useful in the formulations ofcertain embodiments of the present invention include starch, modifiedstarch, and starch derivatives, gums, including but not limited toxanthan gum, alginic acid, other alginates, benitoniite, veegum, agar,guar, locust bean gum, gum arabic, quince psyllium, flax seed, okra gum,arabinoglactin, pectin, tragacanth, scleroglucan, dextran, amylose,amylopectin, dextrin, etc., cross-linked polyvinylpyrrolidone,ion-exchange resins, such as potassium polymethacrylate, carrageenan,kappa-carrageenan, lambda-carrageenan, gum karaya, biosynthetic gum, andmixtures thereof. Other pore-formers include materials useful for makingmicroporous lamina in the environment of use, such as polycarbonatescomprised of linear polyesters of carbonic acid in which carbonategroups reoccur in the polymer chain, microporous materials such asbisphenol, a microporous poly(vinylchloride), micro-porous polyamides,microporous modacrylic copolymers, microporous styrene-acrylic and itscopolymers, porous polysulfones, halogenated poly(vinylidene),polychloroethers, acetal polymers, polyesters prepared by esterificationof a dicarboxylic acid or anhydride with an alkylene polyol,poly(alkylenesulfides), phenolics, polyesters, asymmetric porouspolymers, cross-linked olefin polymers, hydrophilic microporoushiomopolymers, copolymers or interpolymers having a reduced bulkdensity, and other similar materials, poly(urethane), cross-linkedchain-extended poly(urethane), poly(imides), poly(benzimidazoles),collodion, regenerated proteins, semi-solid cross-linkedpoly(vinylpyrrolidone), and mixtures thereof.

In general, the amount of pore-former included in the taste maskingcoatings of certain embodiments of the matrix dosage forms can be fromabout 0.1% to about 80%, by weight including all values and rangestherebetween, relative to the combined weight of polymer andpore-former. The percentage of pore former as it relates to the dryweight of the taste-masking polymer, can have an influence on the drugrelease properties of the coated matrix. In at least one embodiment thatuses water soluble pore formers such as hydroxypropylmethylcellulose, ataste masking polymer: pore former dry weight ratio of from about 10:1to about 1:1 including all values and ranges therebetween can bepresent. In certain embodiments the taste masking polymer: pore formerdry weight ratio is from about 8:1 to about 1.5:1 including all valuesand ranges therebetween; and in other embodiments from about 6:1 toabout 2:1 including all values and ranges therebetween. In at least oneembodiment using EUDRAGIT® NE30D as the taste masking polymer and ahydroxypropylmethylcellulose (approx 5 cps viscosity (in a 2% aqueoussolution)) such as METHOCEL® E5, PHARMACOAT® 606G as the water solublepore former, a taste masking polymer: pore former dry weight ratio ofabout 2:1 is present.

Colorants that can be used in the taste-masking coating of certainembodiments of the matrix dosage forms include food, drug and cosmeticcolors (FD&C), drug and cosmetic colors (D&C) or external drug andcosmetic colors (Ext. D&C). These colors are dyes, lakes, and certainnatural and derived colorants. Useful lakes include dyes absorbed onaluminum hydroxide or other suitable carriers.

Flavorants that can be used in the taste-masking coating of certainembodiments of the matrix dosage forms include natural and syntheticflavoring liquids. An illustrative list of such flavorants includesvolatile oils, synthetic flavor oils, flavoring aromatics, oils,liquids, oleoresins and extracts derived from plants, leaves, flowers,fruits, stems and combinations thereof. A non-limiting representativelist of these includes citric oils, such as lemon, orange, grape, limeand grapefruit, and fruit essences, including apple, pear, peach, grape,strawberry, raspberry, cherry, plum, pineapple, apricot, or other fruitflavors. Other useful flavorants include aldehydes and esters, such asbenzaldehyde (cherry, almond); citral, i.e., alpha-citral (lemon, lime);neral, i.e., beta-citral (lemon, lime); decanal (orange, lemon);aldehyde C-8 (citrus fruits); aldehyde C-9 (citrus fruits); aldehydeC-12 (citrus fruits); tolyl aldehyde (cherry, almond);2,6-dimethyloctanal (green fruit); 2-dodenal (citrus mandarin); andmixtures thereof.

Sweeteners that can be used in the taste-masking coating of certainembodiments of the matrix dosage forms include glucose (corn syrup),dextrose, invert sugar, fructose, and mixtures thereof (when not used asa carrier); saccharin and its various salts, such as sodium salt;dipeptide sweeteners such as aspartame; dihydrochalcone compounds,glycyrrhizin; Steva Rebaudiana (Stevioside); chloro derivatives orsucrose such as sucralose; and sugar alcohols such as sorbitol,mannitol, xylitol, and the like. Also contemplated are hydrogenatedstarch hydrolysates and the synthetic sweeteners such as3,6-dihydro-6-methyl-1-1-1,2,3-oxathiazin-4-1-2,2-dioxide, particularlythe potassium salt (acesulfame-K), and sodium and calcium salts thereof.The sweeteners can be used alone or in any combination thereof.

The matrix taste masking coat can also include one or morepharmaceutically acceptable excipients such as lubricants, emulsifiers,anti-foaming agents, plasticizers, solvents and the like.

Lubricants can be included to help reduce friction of coated matricesduring manufacturing. The lubricants that can be used in the tastemasking coat of certain embodiments of the present invention include butare not limited to adipic acid, magnesium stearate, calcium stearate,zinc stearate, calcium silicate, magnesium silicate, hydrogenatedvegetable oils, sodium chloride, sterotex, polyoxyethylene, glycerylmonostearate, talc, polyethylene glycol, sodium benzoate, sodium laurylsulfate, magnesium lauryl sulfate, sodium stearyl fumarate, lightmineral oil, waxy fatty acid esters such as glyceryl behenate, (e.g.COMPRITOL™), STEAR-O-WET™, MYVATEX™ TL and mixtures thereof. In at leastone embodiment, the lubricant is selected from magnesium stearate, talcand a mixture thereof. The lubricant can be present in an amount of fromabout 1% to about 100% by weight of the polymer dry weight in the tastemasking coat including all values and ranges therebetween. For example,in certain embodiments wherein the taste masking polymer is EUDRAGIT®NE30D or EUDRAGIT® NE40D together with a hydrophilic pore former, thelubricant is present in an amount of from about 1% to about 30% byweight of the polymer dry weight including all values and rangestherebetween; in other embodiments from about 2% to about 20% includingall values and ranges therebetween; and in still other embodiments atabout 10% by weight of the matrix taste masking coat dry weight. Inanother embodiment where the taste masking polymer is ethylcellulose(ETHOCEL™ PR100, PR45, PR20, PR10 or PR7 polymer, or a mixture thereof),the lubricant can be present in an amount of from about 10% to about100% by weight of the matrix taste-masking coat dry weight including allvalues and ranges therebetween; in another embodiment from about 20% toabout 80% including all values and ranges therebetween; and in stillanother embodiments at about 50% by weight of the matrix taste maskingcoat dry weight. In other embodiments, the taste masking coat does notinclude a pore former.

Emulsifying agent(s) (also called emulsifiers or emulgents) can beincluded in the matrix taste masking coat to facilitate actualemulsification during manufacture of the coat, and also to ensureemulsion stability during the shelf-life of the product. Emulsifyingagents useful for the matrix taste masking coat composition of certainembodiments include, but are not limited to naturally occurringmaterials and their semi synthetic derivatives, such as thepolysaccharides, as well as glycerol esters, cellulose ethers, sorbitanesters (e.g. sorbitan monooleate or SPAN™ 80), and polysorbates (e.g.TWEEN™ 80). Combinations of emulsifying agents are operable. In at leastone embodiment, the emulsifying agent is TWEEN™ 80. The emulsifyingagent(s) can be present in an amount of from about 0.01% to about 5% byweight of the matrix taste masking polymer dry weight including allvalues and ranges therebetween. For example, in certain embodiments theemulsifying agent is present in an amount of from about 0.05% to about3% including all values and ranges therebetween; in other embodimentsfrom about 0.08% to about 1.5% including all values and rangestherebetween, and in still other embodiments at about 0.1% by weight ofthe matrix taste masking polymer dry weight.

Anti-foaming agent(s) can be included in the matrix taste masking coatto reduce frothing or foaming during manufacture of the coat.Anti-foaming agents useful for the coat composition include, but are notlimited to simethicone, polyglycol, silicon oil, and mixtures thereof.In at least one embodiment the anti-foaming agent is Simethicone C. Theanti-foaming agent can be present in an amount of from about 0.1% toabout 10% of the matrix taste masking coat weight including all valuesand ranges therebetween. For example, in certain embodiments theanti-foaming agent is present in an amount of from about 0.2% to about5% including all values and ranges therebetween; in other embodimentsfrom about 0.3% to about 1% including all values and rangestherebetween, and in still other embodiments at about 0.6% by weight ofthe matrix taste masking polymer dry weight.

Plasticizer(s) can be included in the matrix taste masking coat toprovide increased flexibility and durability during manufacturing.Plasticizers that can be used in the matrix taste masking coat ofcertain embodiments include acetylated monoglycerides; acetyltributylcitrate, butyl phthalyl butyl glycolate; dibutyl tartrate; diethylphthalate; dimethyl phthalate; ethyl phthalyl ethyl glycolate; glycerin;propylene glycol; triacetin; tripropioin; diacetin; dibutyl phthalate;acetyl monoglyceride; acetyltriethyl citrate, polyethylene glycols;castor oil; rape seed oil, olive oil, sesame oil, triethyl citrate;polyhydric alcohols, glycerol, glycerin sorbitol, acetate esters,gylcerol triacetate, acetyl triethyl citrate, dibenzyl phthalate,dihexyl phthalate, butyl octyl phthalate, diisononyl phthalate, butyloctyl phthalate, dioctyl azelate, epoxidized tallate, triisoctyltrimellitate, diethylhexyl phthalate, di-n-octyl phthalate, di-i-octylphthalate, di-i-decyl phthalate, di-n-undecyl phthalate, di-n-tridecylphthalate, tri-2-ethylhexyl trimellitate, di-2-ethylhexyl adipate,di-2-ethylhexyl sebacate, di-2-ethylhexyl azelate, dibutyl sebacate,diethyloxalate, diethylmalate, diethylfumerate, dibutylsuccinate,diethylmalonate, dibutylphthalate, dibutylsebacate, glyceroltributyrate,and mixtures thereof. The plasticizer can be present in an amount offrom about 1% to about 80% of the taste masking polymer dry weightincluding all values and ranges therebetween. For example, in certainembodiments the plasticizer is present in an amount of from about 5% toabout 50% including all values and ranges therebetween, in otherembodiments from about 10% to about 40% including all values and rangestherebetween, and in still other embodiments at about 20% of the tastemasking polymer dry weight.

In some embodiments mixtures of plasticizers are provided, e.g., amixture of PEG 4000 and Dibutyl Sebacate (DBS). For example, in a 174 mgbupropion hydrobromide tablet, PEG4000 is present in an amount of 1.6%by weight of the total formulation and DBS is present in an amount of0.8% by weight of the total formulation, in a 348 mg bupropionhydrobromide tablet, PEG4000 is present in an amount of 0.9% by weightof the total formulation and DBS is present in an amount of 0.4% byweight of the total formulation, and in a 522 mg bupropion hydrobromidetablet, PEG4000 is present in an amount of 0.9% by weight of the totalformulation and DBS is present in an amount of 0.4% by weight of thetotal formulation,

The taste-masking coating can be present in an amount of from about 1%to about 90% by weight of the matrix including all values and rangestherebetween, depending upon the choice of polymer, the ratio ofpolymer:pore former, and the total surface area of the matrixformulation. Since a certain thickness of taste masking coating has tobe achieved in order to achieve effective taste masking, the amount oftaste masking polymer coating used during manufacture is related to thetotal surface area of the batch of uncoated matrices that requires acoating. For example, the taste masking polymer surface area coveragecan range from about 0.5 mg/cm2 to about 20 mg/cm2 including all valuesand ranges therebetween. For example, in certain embodiments the surfacearea coverage of the taste masking polymer is from about 0.6 mg/cm2 toabout 10 mg/cm2 including all values and ranges therebetween, and inother embodiments is from about 1 mg/cm2 to about 5 mg/cm2 including allvalues and ranges therebetween. In at least one embodiment of theinvention, EUDRAGIT® E is employed as the taste masking polymer at asurface area coverage of about 4 mg/cm2.

In the absence of an accurate determination of total surface area of amatrix, the amount of taste masking polymer to be applied can beexpressed as a percentage of the uncoated matrix. For example, incertain embodiments the taste-masking coating is present in an amount offrom about 5% to about 60% including all values and ranges therebetween;in other embodiments from about 10% to about 40% including all valuesand ranges therebetween; and in still other embodiments from about 15%to about 35% by weight of the matrix including all values and rangestherebetween. In at least one embodiment the taste-masking coating ispresent in an amount of about 30% by weight of the matrix.

Prophetic examples of matrix tablet formulations are described below. Itshould be understood that these examples are intended to be exemplaryand that the specific constituents, amounts thereof, and formulationmethods may be varied therefrom in order to achieve different releasecharacteristics:

In at least one embodiment, the controlled matrices comprise:

Bupropion HBr about 30.0% by weight of the matrixHydroxypropylmethylcellulose E50 about 10.0% by weight of the matrixHydroxypropylmethylcellulose about 30.0% by weight of the matrix K15MCalcium phosphate dehydrate about 9.5% by weight of the matrix ATMUL ™84S about 20.0% by weight of the matrix (mono/di/tri glycerides)Magnesium stearate about 0.5% by weight of the matrix

Preparation of the matrix formulation can be as follows: combine thedrug, a portion of each HPMC, calcium phosphate and Atmul 84S in aplanetary mixer and dry mix for 15 minutes. Add a solution of theremainder of the HPMC in water to the mixer while mixing, until a wetmass is obtained. Pass the wet material through a screen to make theresultant granules of uniform size (to achieve uniform drying) and dryin an oven at about 40° C. for about 24 hours. Mill the dried granulesthrough a Fitzpatrick Mill, knives forward, and collect the material ina mixer. Add the magnesium stearate and mix for about 5 minutes. Theresultant mixture is tabletted on a suitable tablet press.

In at least one embodiment, the controlled release matrices comprise adeposit-core and support-platform. Preparation of the deposit-core canbe as follows: Deposit-cores can be prepared using the followingmaterials in the stated quantities:

Bupropion HBr about 45.0 g hydroxypropylmethylcellulose about 35.0 g(METHOCEL ® K 100M-Colorcon) mannitol about 10.0 g ethylcellulose (highviscosity-BDH) about 3.75 g 3.75 g magnesium stearate about 1.0 g 5:1ethanol-chloroform mixture about 75.0 ml

The bupropion hydrobromide is mixed intimately with the mannitol andhydroxypropylmethylcellulose in a suitable mixer. The solution ofethylcellulose in ethanol-chloroform is prepared separately, and is usedfor wetting the previously obtained powder mixture. The resultanthomogeneous mass is forced through an 800 micron screen and then driedto obtain a granulate which is passed through a 420 micron screen. Thehomogeneous granulate obtained is mixed with the magnesium stearate andthen compressed using concave punches of diameter 7 mm (radius ofcurvature 9 mm) using a pressure of about 3000 kg/cm2 to obtaincylindrical deposit-cores with convex bases.

Application of the support-platform can be as follows: Thesupport-platform can be applied by coating one or both the convex basesof the deposit-core with a solution of about 15g low-permeabilityacrylic-methacrylic copolymer (EUDRAGIT® RS) in methylene chloride of aquantity to make up to 100 ml. Thereafter about 0.3 ml of said solutionis applied to each base to be covered, taking care to protect thelateral core surface. The system is then dried with tepid air. Thequantity of polymeric material deposited is sufficient to keep thestructure intact during transfer.

In at least one embodiment, the matrix formulation is a polyethyleneoxide (PEO) based tablet matrix formulation comprising:

Bupropion Hydrobromide about 50% PEO WSR Coagulant about 15%(polyethylene oxide) METHOCEL ® K100M about 15% (hydroxypropylmethylcellulose) Avicel PH101 about 19% (microcrystalline cellulose) MagnesiumStearate about 1%

Preparation of the PEO based tablet matrix formulation can be asfollows: excipients dry blended in an appropriate mixer and compressedinto tablets using conventional apparatus.

Multiparticulates

In certain embodiments of the present invention, a multiparticulatesystem is provided which contains multiple microparticles eachcontaining an effective amount of bupropion hydrobromide and at leastone pharmaceutically acceptable excipient. The multiparticulates can becontained within a capsule, or can be compressed into a matrix ortablet, that upon ingestion dissolves into multiple units (e.g.pellets), wherein the sub-units or pellets possess the desiredcontrolled release properties of the dosage form. The multiparticulatesor the multiple unit dosage forms can be surrounded by one or morecoatings. Examples of such coatings include polymeric controlled releasecoatings, delayed release coatings, enteric coatings, immediate releasecoatings, taste-masking coatings, extended release coatings, andnon-functional coatings.

The bupropion hydrobromide salt in the microparticles of certainembodiments can be present in an effective amount of from about 0.1% toabout 99% by weight of the microparticles including all values andranges therebetween. For example, in certain embodiments bupropionhydrobromide is present in the microparticles in an amount of from about0.1% to about 90% including all values and ranges therebetween, in otherembodiments from about 5% to about 90% including all values and rangestherebetween, in still other embodiments from about 10% to about 80%including all values and ranges therebetween, and in even still otherembodiments from about 25% to about 80% by weight of the microparticleincluding all values and ranges therebetween. In certain embodimentswherein the microparticles are manufactured using a spheronizationprocess, the bupropion hydrobromide can be present in the microparticlesin an amount of from about 0.1% to about 60% including all values andranges therebetween; in other such embodiments from about 5% to about50% including all values and ranges therebetween; and in still othersuch embodiments from about 10% to about 40% by weight of themicroparticle including all values and ranges therebetween. In at leastone embodiment wherein the microparticles are manufactured using aspheronization process, the bupropion hydrobromide is present in themicroparticle in an amount of about 30% by weight of the microparticle.

In addition to the bupropion hydrobromide salt, the microparticles ofthe present invention also include at least one pharmaceuticallyacceptable excipient. Excipients can be added to facilitate in thepreparation, patient acceptability and functioning of the dosage form asa drug delivery system. Examples of possible excipients includespheronization aids, solubility enhancers, disintegrating agents,diluents, lubricants, binders, fillers, glidants, suspending agents,emulsifying agents, anti-foaming agents, flavoring agents, coloringagents, chemical stabilizers, pH modifiers, and mixtures thereof.Depending on the intended main function, excipients to be used informulating compositions are subcategorized into different groups.However, one excipient can affect the properties of a composition in aseries of ways, and many excipients used in compositions can thus bedescribed as being multifunctional.

The microparticles of certain embodiments of the present invention canbe manufactured using standard techniques known to one of skill in theart. In certain embodiments the microparticles can be made according toany one of the methods described herein. Useful microparticles includedrug-layered microparticles and drug-containing microparticles.

Drug-Containing Microparticles

Microparticles containing drug in the core can be prepared by a numberof different procedures. For example: In a spray drying process, anaqueous solution of core material and hot solution of polymer isatomized into hot air, the water then evaporates, and the dry solid isseparated in the form of pellets, for example by air suspension. Aspray-drying process can produce hollow pellets when the liquidevaporates at a rate that is faster than the diffusion of the dissolvedsubstances back into the droplet interior, or if due to capillary actionthe dissolved substance migrates out with the liquid to the dropletsurface, leaving behind a void. Another example is a spray congealingprocess, where a slurry of drug material that is insoluble in a moltenmass is spray congealed to obtain discrete particles of the insolublematerials coated with the congealed substance. A further example is afluidized bed based granulation/pelletization process, where a dry drugis suspended in a stream of hot air to form a constantly agitatedfluidized bed. An amount of binder or granulating liquid is thenintroduced in a finely dispersed form to cause pelletization.

The drug-containing microparticles of certain embodiments of the presentinvention can also be made by, for example, a spheronization process.One method of manufacturing the drug-containing microparticles is theapplicant's proprietary CEFORM™ (Centrifugally Extruded & FormedMicrospheres/Microparticles) technology, which is the simultaneous useof flash heat and centrifugal force, using proprietary designedequipment, to convert dry powder systems into microparticles of uniformsize and shape. The production of microparticles containing an activedrug using this CEFORM™ technology is known. Certain embodiments of thepresent invention deal with the use of LIQUIFLASH® processing tospheronize compositions containing one or more active drugs to formLIQUIFLASH® microparticles.

With the CEFORM™ technology, the processing of the drug-containingmicroparticles of certain embodiments of the present invention iscarried out in a continuous fashion, whereby a pre-blend of drug andexcipients is fed into a spinning “microsphere head”, also termed as a“spheronizing head”. The microsphere head, which is a multi-apertureproduction unit, spins on its axis and is heated by electrical power.The drug and excipient(s) pre-blend is fed into the center of the headwith an automated feeder. The material moves, via centrifugal force, tothe outer rim where the heaters, located in the rim of the head, heatthe material. Microparticles are formed when the molten material exitsthe head, which are then cooled by convection as they fall to the bottomof the microparticle chamber. The product is then collected and storedin suitable product containers. Careful selection of the types andlevels of excipient(s) control microparticle properties such assphericity, surface morphology, and dissolution rate. One advantage ofsuch a process is that the microparticles are produced and collectedfrom a dry feedstock without the use of any solvents.

There are at least two approaches that can be used to producedrug-containing microparticles using the CEFORM process: (i) theencapsulation approach and (ii) the co-melt approach. In theencapsulation approach, the process is conducted below the melting pointof the drug. Therefore, the excipients are designed to melt and entrainthe drug particles on passing through the apertures to formmicroparticles. The resulting microparticles contain the drug, in itsnative state, essentially enveloped by or as an intimate matrix with theresolidified excipients. In the co-melt approach, the process isconducted above the melting point of the drug. In this case, the drugand the excipients melt or become fluid simultaneously upon exposure tothe heat. The molten mixture exits the head and forms microparticles,which cool as they fall to the bottom of the collection bin where theyare collected.

In at least one embodiment the microparticles are manufactured using theencapsulation approach. In the encapsulation approach the excipient(s)which are chosen have a lower melting point than the drug (e.g.bupropion hydrobromide) with which they will be combined. Therefore thespheronizing process can be performed at lower temperatures, than themelting point of the drug. As a result, this can reduce the risk ofpolymeric interconversion, which can occur when using processingtemperatures close to the melting point.

In a prophetic example of certain embodiments of the present invention,the manufacturing process for the microparticles can hypothetically beas follows: Spheronization aid is screened through a 425 micron (μm)screen. In at least one embodiment, the spheronization aid is distilledglyceryl monostearate (i.e. DMG-03VF). About 50% of the spheronizationaid is added to a bowl in a high shear mixer. In at least oneembodiment, the bowl is a 6 litre bowl and the high shear mixer is aDiosna P1-6 high speed mixer granulator. The active drug is then addedto the bowl of the mixer, and then the remainder of the spheronizationaid is added. The material is then blended in the mixer for a time fromabout 1 minute to about 30 minutes including all values and rangestherebetween; in certain embodiments from about 3 minutes to about 10minutes; and in at least one embodiment at about 6 minutes. The mixermotor speed is from about 50 rpm to about 2000 rpm including all valuesand ranges therebetween; in certain embodiments from about 200 rpm toabout 500 rpm; and in at least one embodiment at about 300 rpm. Thechopper motor speed is from about 50 rpm to about 2000 rpm including allvalues and ranges therebetween; in certain embodiments from about 200rpm to about 500 rpm; and in at least one embodiment at about 400 rpm.The blended material is then spheronized in a CEFORM™ spheronizing head.The spheronizing head speed is from about 5 Hz to about 60 Hz includingall values and ranges therebetween; in certain embodiments from about 10Hz to about 30 Hz; and in at least one embodiment at about 15 Hz. In atleast one embodiment the CEFORM™ spheronizing head is a 5 inch head. Thespheronizing head temperature is maintained at a temperature from about70° C. to about 130° C. including all values and ranges therebetween; incertain embodiments from about 90° C. to about 110° C.; and in at leastone embodiment at about 100° C. The microparticles obtained from thespinning process are then screened through a screen that is from about150 μm to about 800 μm including all values and ranges therebetween.

For microparticles manufactured using a spheronization process such asthe CEFORM™ process, the microparticles include, in addition to thebupropion hydrobromide salt, at least one spheronization aid.Spheronization aids can assist the drug-containing mix to form robustdurable spherical particles. Some examples of materials useful asspheronization aids include, but are not limited to glycerylmonostearate, glyceryl behenate, glyceryl dibehenate, glycerylpalmitostearate, hydrogenated oils such as hydrogenated castor oilmarketed under the name CUTINA™ HR, fatty acid salts such as magnesiumor calcium stearate, polyols such as mannitol, sorbitol, xylitol,stearic acid, palmitic acid, sodium lauryl sulfate, polyoxyethyleneethers, esterified polyoxyethylenes such as PEG-32 distearate, PEG-150distearate, cetostearyl alcohol, waxes (e.g. carnauba wax, white wax,paraffin wax) and wax-like materials. Certain thermo-plastic orthermo-softening polymers can also function as spheronization aids. Somenon-limiting examples of such thermo-plastic or thermo-softeningpolymers include Povidone, cellulose ethers and polyvinylalcohols.Combinations of spheronization aids can be used. In at least oneembodiment, the spheronization aid includes glyceryl monostearate (i.e.DMG-03VF). The spheronization aid can be present in an amount of fromabout 0.1% to about 99% by weight of the microparticle including allvalues and ranges therebetween. For example, in certain embodiments thespheronization aid is present in an amount of from about 5% to about 90%including all values and ranges therebetween; in other embodiments fromabout 10% to about 80% including all values and ranges therebetween; instill other embodiments from about 20% to about 70% including all valuesand ranges therebetween; and in even still other embodiments from about30% to about 60% by weight of the microparticle including all values andranges therebetween. In at least one embodiment the spheronization aidis present in an amount of about 50% by weight of the microparticle. Inat least one other embodiment, the microparticles include about 50%(w/w) of bupropion hydrobromide and about 50% (w/w) of thespheronization aid.

In certain embodiments, each microparticle can also include at least onesolubility enhancer. Solubility enhancers can be surfactants. Certainembodiments of the invention include a solubility enhancer that is ahydrophilic surfactant. Hydrophilic surfactants can be used to provideany of several advantageous characteristics to the compositions,including: increased solubility of the bupropion hydrobromide salt inthe microparticle; improved dissolution of the bupropion hydrobromidesalt; improved solubilization of the bupropion hydrobromide salt upondissolution; enhanced absorption and/or bioavailability of the bupropionhydrobromide salt. The hydrophilic surfactant can be a singlehydrophilic surfactant or a mixture of hydrophilic surfactants, and canbe ionic or non-ionic.

Likewise, various other embodiments of the invention include alipophilic component, which can be a lipophilic surfactant, including amixture of lipophilic surfactants, a triglyceride, or a mixture thereof.The lipophilic surfactant can provide any of the advantageouscharacteristics listed above for hydrophilic surfactants, as well asfurther enhancing the function of the surfactants. These variousembodiments are described in more detail below.

As is well known in the art, the terms “hydrophilic” and “lipophilic”are relative terms. To function as a surfactant, a compound includespolar or charged hydrophilic moieties as well as non-polar hydrophobic(lipophilic) moieties; i.e., a surfactant compound is amphiphilic. Anempirical parameter commonly used to characterize the relativehydrophilicity and lipophilicity of non-ionic amphiphilic compounds isthe hydrophilic-lipophilic balance (the “HLB” value). Surfactants withlower HLB values are more lipophilic, and have greater solubility inoils, whereas surfactants with higher HLB values are more hydrophilic,and have greater solubility in aqueous solutions.

Using HLB values as a rough guide, hydrophilic surfactants can generallybe considered to be those compounds having an HLB value greater thanabout 10, as well as anionic, cationic, or zwitterionic compounds forwhich the HLB scale is not generally applicable. Similarly, lipophilicsurfactants can be compounds having an HLB value less than about 10.

It should be appreciated that the HLB value of a surfactant is merely arough guide generally used to enable formulation of industrial,pharmaceutical and cosmetic emulsions. For many surfactants, includingseveral polyethoxylated surfactants, it has been reported that HLBvalues can differ by as much as about 8 HLB units, depending upon theempirical method chosen to determine the HLB value (Schott, J. Pharm.Sciences, 79(1), 87-88 (1990)). Likewise, for certain polypropyleneoxide containing block copolymers (poloxamers, available commercially asPLURONIC® surfactants), the HLB values may not accurately reflect thetrue physical chemical nature of the compounds. Finally, commercialsurfactant products are generally not pure compounds, but are oftencomplex mixtures of compounds, and the HLB value reported for aparticular compound may more accurately be characteristic of thecommercial product of which the compound is a major component. Differentcommercial products having the same primary surfactant component can,and typically do, have different HLB values. In addition, a certainamount of lot-to-lot variability is expected even for a singlecommercial surfactant product. Keeping these inherent difficulties inmind, and using HLB values as a guide, one skilled in the art canreadily identify surfactants having suitable hydrophilicity orlipophilicity for use in the present invention, as described herein.

Solubility enhancers can be any surfactant suitable for use inpharmaceutical compositions as known in the art. Suitable surfactantscan be anionic, cationic, zwitterionic or non-ionic. Refined, distilledor fractionated surfactants, purified fractions thereof, orre-esterified fractions, are within the scope of the invention.

Although polyethylene glycol (PEG) itself does not function as asurfactant, a variety of suitable PEG-fatty acid esters have usefulsurfactant properties, as is known in the art. Polyethylene glycol (PEG)fatty acid diesters are also suitable for use as surfactants in thecompositions of the present invention, as is known in the art. Ingeneral, mixtures of surfactants are also useful in the presentinvention, including mixtures of two or more commercial surfactantproducts as is known in the art (e.g. PEG-fatty acid esters are marketedcommercially as mixtures or mono- and diesters).

A large number of suitable surfactants of different degrees oflipophilicity or hydrophilicity can be prepared by reaction of alcoholsor polyalcohols with a variety of natural and/or hydrogenated oils, asis known in the art. In certain embodiments, the oils used are castoroil or hydrogenated castor oil or an edible vegetable oil such as cornoil, olive oil, peanut oil, palm kernel oil, apricot kernel oil, oralmond oil. Non-limiting examples of alcohols include glycerol,propylene glycol, ethylene glycol, polyethylene glycol, sorbitol,pentaerythritol and mixtures thereof.

Polyglycerol esters of fatty acids as is known in the art, are alsosuitable surfactants for the present invention. Esters of propyleneglycol and fatty acids as is known in the art are also suitablesurfactants for use in the present invention. In general, mixtures ofsurfactants are also suitable for use in the present invention. Inparticular, mixtures of propylene glycol fatty acid esters and glycerolfatty acid esters, as is known in the art, are suitable and arecommercially available. Another class of suitable surfactants is theclass of mono- and diglycerides, as are known in the art. Thesesurfactants are generally lipophilic. Sterols and derivatives of sterolsare also suitable surfactants for use in the present invention as isknown in the art. These surfactants can be hydrophilic or lipophilic. Avariety of PEG-sorbitan fatty acid esters are known in the art and areavailable and suitable for use as surfactants in the present invention.In general, these surfactants are hydrophilic, although severallipophilic surfactants of this class can be used. Suitable ethers ofpolyethylene glycol and alkyl alcohols are known in the art and aresuitable surfactants for use in the present invention. Esters of sugarsare known in the art and are suitable surfactants for use in the presentinvention. Several hydrophilic PEG-alkyl phenol surfactants are known inthe art and are available, and are suitable for use in the presentinvention.

The POE-POP block copolymers are a unique class of polymericsurfactants. The unique structure of the surfactants, with hydrophilicPOE and lipophilic POP moieties in well-defined ratios and positions,provides a wide variety of surfactants suitable for use in the presentinvention. These surfactants are available under various trade names,including SYNPERONIC™ PE series (ICI); PLURONIC® series, EMKALYX™,LUTROL™, SUPRONIC™ MONOLAN™, PLURACARE™, and PLURODAC™. The generic termfor these polymers is “poloxamer” (CAS 9003-11-6). These polymers havethe formula: HO(C2H4O)a(C3H6O)b(C2H4O)aH where “a” and “b” denote thenumber of polyoxyethylene and polyoxypropylene units, respectively. Thesuitable surfactants of this class are known in the art.

Sorbitan esters of fatty acids are suitable surfactants for use in thepresent invention and are known in the art. Esters of lower alcohols (C2to C4) and fatty acids (C8 to C18) are suitable surfactants for use inthe present invention and are known in the art. Ionic surfactants,including cationic, anionic and zwitterionic surfactants, are suitablehydrophilic surfactants for use in the present invention and are knownin the art. In certain embodiments, the surfactant is an anionicsurfactant such as a fatty acid salt, a bile salt, or a combinationthereof. In other embodiments the surfactant is a cationic surfactantsuch as a carnitine.

Examples of ionic surfactants include sodium oleate, sodium laurylsulfate, sodium lauryl sarcosinate, sodium dioctyl sulfosuccinate,sodium cholate, sodium taurocholate; lauroyl carnitine; palmitoylcarnitine; and myristoyl carnitine.

Ionizable surfactants, when present in their unionized (neutral,non-salt) form, are lipophilic surfactants suitable for use in thecompositions of the present invention, and are known in the art.Particular examples of such surfactants include free fatty acids,particularly C6-C22 fatty acids, and bile acids. More specifically,suitable unionized ionizable surfactants include the free fatty acid andbile acid forms of any of the fatty acid salts and bile salts.

Derivatives of oil-soluble vitamins, such as vitamins A, D, E, K, etc.,are also useful surfactants for the compositions of the presentinvention. An example of such a derivative is tocopheryl PEG-1000succinate (TPGS).

In certain embodiments, surfactants or mixtures of surfactants thatsolidify at ambient room temperature are used. In other embodiments,surfactants or mixtures of surfactants that solidify at ambient roomtemperature in combination with particular lipophilic components, suchas triglycerides, or with addition of appropriate additives, such asviscosity modifiers, binders, thickeners, and the like, are used.

Examples of non-ionic hydrophilic surfactants include alkylglucosides;alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides;polyoxyethylene alkyl ethers; polyoxyethylene alkylphenols; polyethyleneglycol fatty acids esters; polyethylene glycol glycerol fatty acidesters; polyoxyethylene sorbitan fatty acid esters;polyoxyethylene-polyoxypropylene block copolymers; polyglycerol fattyacid esters; polyoxyethylene glycerides; polyoxyethylene sterols,derivatives, and analogues thereof; polyoxyethylene vegetable oils;polyoxyethylene hydrogenated vegetable oils; reaction mixtures ofpolyols with fatty acids, glycerides, vegetable oils, hydrogenatedvegetable oils, and sterols; sugar esters, sugar ethers;sucroglycerides; polyethoxylated fat-soluble vitamins or derivatives;and mixtures thereof.

In certain embodiments, the non-ionic hydrophilic surfactant is selectedfrom the group comprising polyoxyethylene alkylethers; polyethyleneglycol fatty acids esters; polyethylene glycol glycerol fatty acidesters; polyoxyethylene sorbitan fatty acid esters;polyoxyethylene-polyoxypropylene block copolymers; polyglyceryl fattyacid esters; polyoxyethylene glycerides; polyoxyethylene vegetable oils;polyoxyethylene hydrogenated vegetable oils, and mixtures thereof. Theglyceride can be a monoglyceride, diglyceride, triglyceride, or amixture thereof.

In certain other embodiments, the surfactants used are non-ionichydrophilic surfactants that are reaction mixtures of polyols and fattyacids, glycerides, vegetable oils, hydrogenated vegetable oils orsterols. These reaction mixtures are largely composed of thetransesterification products of the reaction, along with often complexmixtures of other reaction products. The polyol can be glycerol,ethylene glycol, polyethylene glycol, sorbitol, propylene glycol,pentaerythritol, a saccharide, or a mixture thereof.

The hydrophilic surfactant can also be, or include as a component, anionic surfactant. Examples of ionic surfactants include alkyl ammoniumsalts; bile acids and salts, analogues, and derivatives thereof; fusidicacid and derivatives thereof; fatty acid derivatives of amino acids,oligopeptides, and polypeptides; glyceride derivatives of amino acids,oligopeptides, and polypeptides; acyl lactylates; mono-,diacetylatedtartaric acid esters of mono-, diglycerides; succinylatedmonoglycerides; citric acid esters of mono-,diglycerides; alginatesalts; propylene glycol alginate; lecithins and hydrogenated lecithins;lysolecithin and hydrogenated lysolecithins; lysophospholipids andderivatives thereof; phospholipids and derivatives thereof salts ofalkylsulfates; salts of fatty acids; sodium docusate; carnitines; andmixtures thereof.

In certain embodiments the ionic surfactants include bile acids andsalts, analogues, and derivatives thereof; lecithins, lysolecithin,phospholipids, lysophospholipids and derivatives thereof salts ofalkylsulfates; salts of fatty acids; sodium docusate; acyl lactylates;mono-, diacetylated tartaric acid esters of mono-, diglycerides;succinylated monoglycerides; citric acid esters of mono-diglycerides;carnitines; and mixtures thereof.

Examples of ionic surfactants include lecithin, lysolecithin,phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol,phosphatidic acid, phosphatidylserine, lysophosphatidylcholine,lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidicacid, lysophosphatidylserine, PEG-phosphatidylethanolamine,PVP-phosphatidylethanolamine, lactylic esters of fatty acids,stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides,mono/diacetylated tartaric acid esters of mono/diglycerides, citric acidesters of mono/diglycerides, cholate, taurocholate, glycocholate,deoxycholate, taurodeoxycholate, chenodeoxycholate, glycodeoxycholate,glycochenodeoxycholate, taurochenodeoxycholate, ursodeoxycholate,tauroursodeoxycholate, glycoursodeoxycholate, cholylsarcosine, N-methyltaurocholate, caproate, caprylate, caprate, laurate, myristate,palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, laurylsulfate, teracecyl sulfate, docusate, lauroyl carnitines, palmitoylcarnitines, myristoyl carnitines, and salts and mixtures thereof.

In certain embodiments, ionic surfactants used include lecithin,lysolecithin, phosphatidylcholine, phosphatidylethanolamine,phosphatidylglycerol, lysophosphatidylcholine,PEG-phosphatidylethanolamine, lactylic esters of fatty acids,stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides,mono/diacetylated tartaric acid esters of mono/diglycerides, citric acidesters of mono/diglycerides, cholate, taurocholate, glycocholate,deoxycholate, taurodeoxycholate, glycodeoxycholate, cholylsarcosine,caproate, caprylate, caprate, laurate, oleate, lauryl sulfate, docusate,and salts and mixtures thereof. In at least one embodiment, the ionicsurfactant is selected from lecithin, lactylic esters of fatty acids,stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides,mono/diacetylated tartaric acid esters of mono/diglycerides, citric acidesters of mono/diglycerides, taurocholate, caprylate, caprate, oleate,lauryl sulfate, docusate, and salts and mixtures thereof.

Examples of lipophilic surfactants include alcohols; polyoxyethylenealkylethers; fatty acids; glycerol fatty acid esters; acetylatedglycerol fatty acid esters; lower alcohol fatty acids esters;polyethylene glycol fatty acids esters; polyethylene glycol glycerolfatty acid esters; polypropylene glycol fatty acid esters;polyoxyethylene glycerides; lactic acid derivatives ofmono/diglycerides; propylene glycol diglycerides; sorbitan fatty acidesters; polyoxyethylene sorbitan fatty acid esters;polyoxyethylene-polyoxypropylene block copolymers; transesterifiedvegetable oils; sterols; sterol derivatives; sugar esters; sugar ethers;sucroglycerides; polyoxyethylene vegetable oils; polyoxyethylenehydrogenated vegetable oils; and mixtures thereof.

As with the hydrophilic surfactants, lipophilic surfactants can bereaction mixtures of polyols and fatty acids, glycerides, vegetableoils, hydrogenated vegetable oils, and sterols.

In certain embodiments, the lipophilic surfactants include one or moreselected from the group comprising fatty acids; lower alcohol fatty acidesters; polyethylene glycol glycerol fatty acid esters; polypropyleneglycol fatty acid esters; polyoxyethylene glycerides; glycerol fattyacid esters; acetylated glycerol fatty acid esters; lactic acidderivatives of mono/diglycerides; sorbitan fatty acid esters;polyoxyethylene sorbitan fatty acid esters;polyoxyethylene-polyoxypropylene block copolymers; polyoxyethylenevegetable oils; polyoxyethylene hydrogenated vegetable oils; andreaction mixtures of polyols and fatty acids, glycerides, vegetableoils, hydrogenated vegetable oils, sterols, and mixtures thereof.

In certain other embodiments, the lipophilic surfactants include one ormore selected from the group comprising lower alcohol fatty acidsesters; polypropylene glycol fatty acid esters; propylene glycol fattyacid esters; glycerol fatty acid esters; acetylated glycerol fatty acidesters; lactic acid derivatives of mono/diglycerides; sorbitan fattyacid esters; polyoxyethylene vegetable oils; and mixtures thereof. Amongthe glycerol fatty acid esters, the esters can be mono- or diglycerides,or mixtures of mono- and diglycerides, where the fatty acid moiety is aC6 to C22 fatty acid.

Other embodiments include lipophilic surfactants which are the reactionmixture of polyols and fatty acids, glycerides, vegetable oils,hydrogenated vegetable oils, and sterols. Examples of polyols arepolyethylene glycol, sorbitol, propylene glycol, pentaerythritol, andmixtures thereof.

Combinations of solubility enhancers (i.e. surfactants) can be used.Examples of macrogol fatty acid esters useful as solubility enhancersinclude GELUCIRE® 50/13 and GELUCIRE® 44/14. In at least one embodimentthe solubility enhancer is GELUCIRE® 50/13. The solubility enhancer canbe present in an amount of from about 0.1% to about 70% by weight of themicroparticle including all values and ranges therebetween. For example,in certain embodiments, the solubility enhancer is present in an amountof from about 1% to about 50% including all values and rangestherebetween; in other embodiments from about 10% to about 30% includingall values and ranges therebetween; in still other embodiments fromabout 15% to about 25% by weight of the microparticle including allvalues and ranges therebetween. In at least one embodiment thesolubility enhancer is present in an amount of about 20% by weight ofthe microparticle.

It is contemplated that in some embodiments, one or more otherpharmaceutically acceptable excipients consistent with the objects ofthe present invention can be used in the microparticles, such as alubricant, a binder, a pH modifier, a filler and/or a glidant.

The process for manufacturing the drug-containing microparticles ofcertain embodiments of the present invention by spheronization are notlimited to the CEFORM™ technology, and any other technology resulting inthe formation of the microparticles consistent with the objects of thepresent invention can also be used. For example, microparticles ofcertain embodiments of the invention can also be manufactured byextrusion/spheronization, granulation or pelletization.

Extrusion/spheronization is a multi-step process used to make uniformlysized spherical particles. The technique offers the ability toincorporate high levels of active ingredients without producingexcessively large particles. The main steps in the process are:

Dry-mixing of ingredients to achieve a homogenous powder dispersion;Wet massing using for example a high-shear wet granulator to form rodshaped particles of uniform diameter;Extrusion to form rod-shaped particles of uniform diameter;Spheronization to round off the rods into spherical particles;Screening to achieve the desired narrow particle size distribution.

The mixing vessel used for dry-mixing can be of any size and shapecompatible with the size of the formulation to be produced. For example,commercially available mixing devices such as planetary mixers, highshear mixers, or twin cone blenders can be used. If relatively smallquantities of formulation are to be prepared, a simple mortar and pestlecan be sufficient to mix the ingredients. The type of mixing vesselwould be apparent to one skilled in the pharmaceutical art. Themoistened mass formed by wet-massing in conventional granulationequipment is extruded through a perforated mesh in order to producecylindrical filaments.

The port of the meshes can determine the diameter of the filaments. Aport ranging from about 0.2 mm to about 3 mm including all values andranges therebetween, can be used in this process. In at least oneembodiment utilizing this process, the port ranges from about 0.4 mm toabout 2 mm including all values and ranges therebetween. The extrusioncan be carried out using screw, double screw, “sieve and basket” kind,“roll extruder”, “ram extruder” extruders or any other pharmaceuticallyacceptable means to produce cylindrical filaments. In certainembodiments utilizing this extrusion/spheronization process, a doublescrew coaxial extruder is used. The spheronization device comprises ahollow cylinder with a horizontal rotating plate. The filaments arebroken in short segments which are transformed in spherical orquasi-spherical particles on the upper surface of the rotating plate ata velocity ranging from about 200 rpm to about 2,000 rpm including allvalues and ranges therebetween. The particles can be dried in anypharmaceutically acceptable way, such as for example by air drying in astatic condition. The particles are used as they are or they are coatedto obtain granules to use in tablets, capsules, packets or otherpharmaceutical formulations.

A prophetic example of an extrusion/spheronization formulationcomprising bupropion hydrobromide can be as follows: In this example,the bupropion hydrobromide can be present in an amount of from about 1%to about 80% w/w including all values and ranges therebetween. Incertain embodiments within this example, the bupropion hydrobromide ispresent in an amount of from about 1% to about 50% w/w; in otherembodiments from about 10% to about 30%; and in still other embodimentsabout 10% w/w. In this example, the filler can be present in an amountof from about 0% to about 80% w/w including all values and rangestherebetween. In certain embodiments of this example, the filler ispresent in an amount of from about 10% to about 60%; and in otherembodiments at about 40% w/w. In this example, the microcrystallinecellulose can be present in an amount of from about 10% to about 90% w/wincluding all values and ranges therebetween. In certain embodiments ofthis example, the microcrystalline cellulose is present in an amount offrom about 10% to about 70%; and in other embodiments from about 20% toabout 50% w/w. In this example, the binder can be present in an amountof from about 0% to about 10% w/w including all values and rangestherebetween. In certain embodiments of this example, the binder ispresent in an amount of from about 1% to about 8%; and in otherembodiments from about 2% to about 4% w/w. In this example, water can bepresent in an amount of from about 10% to about 80% w/w including allvalues and ranges therebetween. In certain embodiments of this example,water is present in an amount of from about 15% to about 70%; and inother embodiments from about 20% to about 50% w/w. Suitable fillers thatcan be used in this example include but are not limited to calciumphosphate dibasic, tricalcium phosphate, calcium carbonate, starch (suchas corn, maize, potato and rice starches), modified starches (such ascarboxymethyl starch, etc.), microcrystalline cellulose, sucrose,dextrose, maltodextrins, lactose, and fructose. Suitable lubricants thatcan be used in this example include but are not limited to metalstearates (such as calcium, magnesium on zinc stearates), stearic acid,hydrogenated vegetable oils, talc, starch, light mineral oil, sodiumbenzoate, sodium chloride, sodium lauryl sulfate, magnesium laurylsulfate, sodium stearyl fumarate, glyceryl behenate and polyethyleneglycol (such as CARBOWAX™ 4000 and 6000). Suitable antiadherents in thisexample include but are not limited to colloidal silicon dioxide.Suitable binders in this example include but are not limited to ethylcellulose, a polymethacrylate polymer, polyvinylalcohol, polyvinylpyrrolidone, polyvinylpyrrolidone-vinylacetate copolymer (e.g. KOLLIDON®VA64) hydroxyethylcellulose, low molecular weighthydroxypropylmethylcellulose (e.g. viscosity of about 1-50 cps at about20° C.; about 2-12 cps at about 20° C.; or about 4-6 cps at about 20°C.), hydroxypropylcellulose polymethacrylates, and mixtures thereof.

The drug-containing microparticles formed by extrusion/spheronization inthis prophetic example can be produced using cross-linked amphiphilicpolymers by the following steps: (a) the mixing of one or morecross-linked amphiphilic polymers with bupropion hydrobromide andoptionally other pharmaceutical excipients in order to obtain a uniformmixture in the form of dry powder to which a suitable amount of liquidis added to obtain a pasty consistency; (b) the extrusion of the mixtureobtained from step (a) through a perforated mesh in order to obtaincylindrical filaments having desired length and diameter; (c) thespheronization of the filaments in order to obtain a product in the formof spherical multiparticulates; (d) the drying of the product; and (e)the optional depositing of a drug on the surface of the microparticles.“Cross-linked amphiphilic polymer” refers in this example to polymersshowing characteristics of swellability in the whole pH range of aqueoussolutions and also in solvents or solvent mixtures having differentpolarity characteristics. The polymers can be cross-linked eitherphysically through the interpenetration of the macromolecular meshes, orchemically, thus showing points of link among the macromolecular chains.Non-limiting examples of such polymers include cross-linked polyvinylpyrrolidone, sodium carboxymethylcellulose, sodium glycolate starch anddextrans. Optional excipients include dispersing, emulsifying, wettingagents and coloring agents. The expression “uniform mixture” in thisexample means that the components of the mixture are uniformly dispersedin the formulation by a mixing process which assures the uniformdistribution of each component. A reasonable mixing time can range fromabout 1 to about 60 minutes including all values and rangestherebetween, using one of the mixing equipments conventionally used forthe dry mixing of the powders (e.g. “V”, fixed body, rotating body,sigma mixers). The term “liquid” in this example means any liquidsubstance or mix (solution or emulsion) of liquids of normalpharmaceutical use able to moisten the powder mix, as for example water,aqueous solutions having different pH, organic solvents of normalpharmaceutical use (e.g. alcohols, chlorinated solvents), and oils.Among the oils and surfactants which can be used in this example are:natural oils, either saturated or unsaturated (olive, peanut, soybean,corn, coconut, palm, sesame and similar oils); semisynthetic andsynthetic mono-, di- and triglycerides containing saturated and/orunsaturated fatty acids and their polyhydroxyethylated derivatives(caprico-caprilic triglycerides [MYGLIOL™, CAPTEX™, LABRAFAC™, LIPO™],saturated or unsaturated polyhydroxylated triglycerides of various kind[LABRAFIL™, LABRAFAC™ Hydro, GELUCIRE™]); liquid waxes (isopropylmyristate, isopropyl-caprinate, -caprylate, -laurate, -palmitate,-stearate); fatty acids esters (ethyl oleate, oleyl oleate); siliconeoils; polyethylene glycols (PEG 200, PEG 400, PEG 600, PEG 1000, and soon); polyglycolic glycerides (for example LABRASOL™); polyglycols(propylene glycol, tetraglycol, and ethoxydiglycol (TRANSCUTOL™),sorbitan-esters of fatty acids (for example SPAN®, ARLACEL®, BRIJ®),polyoxyethylenesorbitan esters of fatty acids (for example TWEEN®,CAPMUL®, LIPOSORB®), polypropylene oxide-polyethylene oxide (Poloxamer)copolymers, polyethylene glycol esters (PEG)-glycerol (LABRASOL®,LABRAFIL®), PEG esters and long chain aliphatic acids or alcohols (forexample CREMOPHOR®), polyglycerid esters (PLUROL®), saccharide, fattyacid esters (sucro-esters), and mixtures thereof. Moreover, anionicsurfactants (for example sodium lauryl sulfate, sodium stearate, sodiumoleate) or cationic surfactants (for example tricetol), can be used aswell as lecithins, phospholipids and their semi-synthetic or syntheticderivatives. Also bupropion hydrobromide and/or excipients can bedissolved, dispersed and/or emulsified in such liquids.

In a particular embodiment formed by an extrusion/spheronization processfrom the prophetic example described above, the moistening liquidcomprises an oil/surfactant system wherein the bupropion hydrobromideoptionally emulsified with an aqueous phase is dissolved or dispersed.The amount of liquid with respect to the solid used in the preparationof the mixture can range from about 1% to about 80% by weight includingall values and ranges therebetween. As a prophetic example of thisembodiment, a mixture of bupropion hydrobromide and KOLLIDON™ CL in aratio equal to about 1:3 by weight is co-milled obtaining the mixture inthe form of powder having about 100% of granulometry lower than about 50microns. The mixture is moistened using a liquid demineralized watercontaining KOLLIDON™ 25 (polyvinyl pyrrolidone, BASF) in a solution 3%w/w. The extrusion is carried out forcing the moistened mass through athreader having diameter of the holes equal to about 1 mm. The operativeparameters in this prophetic example can be as follows: powder flowrate: about 4.5 kg/h; liquid flow rate: about 4.1 kg/h; torsionalstress: about 27%; head temperature: about 46° C.; and screw rotationvelocity: about 140 rpm. The extrusion filaments are then processed in aspheronizator adjusted at a velocity equal to about 1,000 rpm for about2 minutes. The obtained microparticles are then dried in a fluid bed forabout 2 hours to a maximum temperature equal to about 59° C. At the endof the drying the product is discharged and is mechanically screenedseparating the fraction ranging from about 0.7 mm to about 1.2 mm.

Another prophetic example of a drug-containing microparticle embodimentof the invention formed by an extrusion/spheronization process, uses acharged resin, the steps of which can comprise: (a) adding the chargedresin, bupropion hydrobromide and other excipients, to a mixing vessel;(b) mixing the ingredients to obtain a uniform mixture; (c) adding agranulating solution—a liquid capable of wetting the dry mixture.Liquids resulting in conversion of the dry powder mixture into a wetgranulation that supports subsequent extrusion and spheronization(marumerization) are included. Typically, water or aqueous solutions areemployed. Alcohols, typically ethanol or isopropanol, can be includedwith the granulating water to enhance the workability of thegranulation. In another embodiment of this invention, one or more of thecomponents of the formulation is first dissolved in water and thissolution is used to produce the wet granulation. An active ingredient oran excipient which is present at very low concentration can initially bedissolved or suspended in the granulating solvent to assure more uniformdistribution throughout the formulation. (d) granulating the mixtureuntil a uniform granulation results; (e) extruding the wet granulationthrough a screen to produce strands of granulation; (f) spheronizing thestrands of granulation to produce spherical multiparticulates; and (g)collecting and drying the spherical multiparticulates. By “chargedresin” is meant in this example to mean a polymer with ionizablefunctional groups that becomes useful in the embodiment of thisinvention. This broadly encompasses any polymer that upon ionization, iscapable of producing cationic or anionic polymeric chains and whichsupport spheronization. Typically from about 10% to about 70% by weightof the spherical multiparticulate is charged resin. Non limitingexamples of these charged resins include sodium polystyrene sulfonate(e.g. AMBERLITE IR-P69™; the chloride salt of cholestyramine resin USP(e.g. AMBERLITE IR-P276™; the acid form of methacrylic acid-divinylbenzene (e.g. AMBERLITE 1RP64™; carboxypolymethylenes (e.g. CARBOPOL™974P and CARBOPOL™ 934P, and sodium polyacrylate (e.g. AQUAKEEP™ J-550.In order for the resin to maintain the desired degree of ionization,agents which produce an acidic or basic environment during granulationand spheronization can be included within the formulation. Among thegroups of compounds that can exert this effect are acids, bases, and thesalts of acids and bases such as adipic acid, citric acid, fumaric acid,tartaric acid, succinic acid, sodium carbonate, sodium bicarbonate,sodium citrate, sodium acetate, sodium phosphates, potassium phosphates,ammonium phosphate, magnesium oxide, magnesium hydroxide, sodiumtartrate, and tromethamine. Certain compounds can be added to thegranulation to provide the proper degree of hydration of the chargedresin, medicament and excipients. These hydrating agents include sugarssuch as lactose, sucrose, mannitol, sorbitol, pentaerythritol, glucoseand dextrose. Polymers such as polyethylene glycol as well assurfactants and other organic and inorganic salts can also be used tomodulate polymer hydration.

In another prophetic example, multiparticulates containing bupropionhydrobromide can be obtained as follows:

Component Percent w/w Bupropion HBr about 8.7 Disodium Phosphate about7.0 Monosodium phosphate about 1.7 Sodium dodecyl sulfate about 21.7Sodium Chloride about 17.4 Povidone 29-32K about 8.7 AMBERLITE IRP-69about 34.8 Butylated Hydroxyanisol about 0.0002

In this prophetic example, approximately 5.75 kg of the aboveformulation is mixed in a planetary mixer for about 15 minutes. Thebutylated hydroxyanisol is dissolved in about 60 cc of ethanol and wateris added to bring the final solution to a volume of about 133 cc. Thissolution is added to the planetary mixer over about a two (2) minuteperiod. The mixer is then granulated with seven aliquots of about 250 ccof water added over about a fifteen minute period. The granulation thusformed is extruded through a 1.0 mm screen and aliquots spheronized bymarumerization at approximately 1200 rpm for approximately 10 minuteseach. The spherical multiparticulates formed are then dried at about 50°C. for about 24 hours.

Another embodiment of this invention involves the production of drugcontaining microparticles in the form of ‘pearls’. Pearls can bemanufactured by mixing bupropion hydrobromide with one or morepharmaceutical excipients in molten form; the melt is forced to passthrough a nozzle which is subjected to a vibration; the pearls formedare allowed to fall in a tower countercurrentwise to a gas; and thesolid pearls are collected in the bottom of the tower. In this example,the quantity of bupropion hydrobromide can vary from about 5% to about95% by weight including all values and ranges therebetween; and incertain embodiments from about 40% to about 60% by weight including allvalues and ranges therebetween. The additives which enable thecrystallization of the supercooled product to be induced in this examplecan be chosen from the following: fatty alcohols such as: cetyl alcohol,stearyl alcohol, fatty acids such as: stearic acid, palmitic acid,glycerol esters such as: glycerol palmitostearate, glycerol stearate(e.g. PRECIROL™), glycerol behenate (e.g. COMPRITOL™), hydrogenated oilssuch as: hydrogenated castor oil (e.g. CUTINA™ HR), fatty acid saltssuch as: magnesium or calcium stearate, polyols such as: mannitol,sorbitol, xylitol, waxes such as: white wax, carnauba wax, paraffin wax,polyoxyethylene glycols of high molecular weight, and esterifiedpolyoxyethylenes such as: PEG-32 distearate, and PEG-150 distearate. Tothese crystallization additives it can be desirable in this example toadd polymers which are soluble or dispersible in the melt, and whichprovide a controlled and adjustable dissolution of the pearls when theyare used, examples of which include: cellulose derivatives(hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethylcellulose, ethyl cellulose, carboxymethyl cellulose), acrylic resins(e.g. EUDRAGIT®), polyvinyl acetates (e.g. RHODOPAS®), polyalkylene(ethylene propylene), polylactic, maleic anhydride, silicone resins, andmixtures thereof. In addition, inorganic additives can be added toaccelerate the solidification of the active substances, examples ofwhich include: silicas, inorganic oxides such as titanium or iron oxide,phosphates, carbonates, clays, and talc. In addition, a surface-activeagent can be added to improve the dispersion of the active substance inthe crystallization additive, examples of which include: sorbitolesters, the polyoxyethylene polysorbates (e.g. TWEEN®), and glycols suchas glycerine or propylene glycol. The process for the preparation ofpearls comprise preparing a melt of the bupropion hydrobromide with oneor more excipients. This melt can be prepared by separately melting thevarious constituents and then mixing them or by melting the mixture ofthe constituents, possible insoluble compounds being added at the end ofthe melting so as to obtain a homogeneous mass. The nature of theconstituents of the melt is chosen by the person skilled in the art,which is considered as a function of the compatibility of theconstituents, the viscosity of the mixture of constituents, the nozzlediameter, the hydrophilicity of the active substance, the surfacetension of the active substance, the particle size of the insolubleadditives, the flow rate of the nozzle, the temperature of the tower,its height and, above all, the size of the desired pearls, theproportion of bupropion hydrobromide to be included therein and thedesired release time of the active substance.

Alternative procedures other than extrusion or spheronization formanufacturing drug-containing microparticles can include wetgranulation, solvent granulation and melt granulation. All of thesetechniques involve the addition of an inactive binder to aggregatesmaller particles into larger granules. For example, wet granulation andsolvent granulation involve the addition of a liquid binder whichaggregates the active materials and excipients into granules. Aftergranulation, the liquid can be removed by a separate drying step. Meltgranulation is similar to wet granulation, but uses a low melting pointsolid material as a binder. The solid binder in melt granulation ismelted and acts as a liquid binder thereby aggregating the powderedactive material and excipients into granules. The binder thereby, can beincorporated into the granules when the granules cool.

Certain embodiments of the present invention include microparticlesmanufactured by a process for producing granules by rotomelt granulationthat comprises mixing bupropion hydrobromide and a powdered excipientmaterial that has a higher melting point than bupropion hydrobromide ina zone wherein both powdered materials are maintained in a fluidizedstate by a rising stream of gas in an apparatus having a rapidlyrotating horizontal-disk located within a vertical vessel having abottom surface; wherein said rapidly rotating disk is located on thebottom surface of the vertical vessel wherein said gas is at atemperature sufficient to cause the bupropion hydrobromide to at leastpartially melt thereby causing said powdered materials to aggregate andform granules. Other embodiments of the present invention includemicroparticles manufactured by a process for producing granules byrotomelt granulation comprising mixing powdered binder material andbupropion hydrobromide wherein the bupropion hydrobromide has a highermelting point than the powdered binder material in a zone wherein bothpowdered materials are maintained in a fluidized state by a risingstream of gas in an apparatus having a rapidly rotating horizontal-disklocated within a vertical vessel having a bottom surface; and whereinsaid rapidly rotating disk is located on the bottom surface of thevertical vessel wherein said gas is at a temperature sufficient to causethe powdered binder material to at least partially melt thereby causingsaid powdered materials to aggregate and form granules.

In rotomelt granulation, one of the feed powders must have a lowermelting point than the other powder in order to serve as a binder. Thefeed powders are introduced into a vertical vessel with rotatablehorizontal-disk located in the bottom of the vessel. The powder ismaintained in fluidized state by at least one stream of filtered airbeing circulated from the bottom of the vertical vessel through one ormore inlets. The rotatable horizontal disk is then rotated while the airsupplied to fluidize the powder is maintained at a temperaturesufficient to soften or melt the lower melting point powder. Thetemperature to which the binder must be heated to soften can beempirically determined by observing the formation of granules at varioustemperatures for various binders. It is presently believed thattemperatures from about 3° C. to about 5° C. below the melting point ormelting range, including all values and ranges therebetween, providessufficient softening to result in granule formation. The lower meltingpoint powder then acts as a binding agent to promote the aggregation ofpowder particles into granules. Suitable powders for use in rotomeltgranulation have a diameter size in the range of from about 5 microns toabout 150 microns including all values and ranges therebetween; and incertain embodiments have a diameter size in the range of about 35microns to about 80 microns. The temperature which the components willbe exposed to depends on the binder employed to aggregate the powders.Generally, the melting point of the binder is above about 30° C.; and incertain embodiments is below about 100° C.

The powders used in these microparticles manufactured by rotomeltgranulation can be formed into granules by at least two alternativegranulation mechanisms. The first mechanism for granule formationutilizes a larger particulate binder and a smaller particulate powder.The temperature during the rotomelt granulation is then elevated only tothe point where the external surface of the binder particles becometacky. As the second powdered material of a smaller size is contactedwith the tacky surface it forms a microlayer on the surface of thebinder particle. This granulation mechanism results in granules whichhave size distribution similar to the original binder particlesemployed. Alternatively, the rotomelt granulation can be conducted at atemperature at which the binder acts as a cement bridging the gapsbetween the unmelted particles (this is referred to as agglomeration).This mechanism results in the formation of granules where the componentsare intermingled. For each binder used the mechanism can be controlledprimarily by the temperature at which the rotomelt granulation isperformed. Those skilled in the art will appreciate that the granulesformed can be observed by electron microscopy to determine the type ofgranulation process occurring. If one particular type of granule isdesired, the process conditions or starting materials can be varied toproduce the desired granules.

In at least one embodiment of the present invention, bupropionhydrobromide is melted to act as a binding agent in the rotomeltgranulation process. Examples of suitable excipients include thoseselected from the following: fillers, lubricants, glidants andantiadherents. Suitable fillers include but are not limited to calciumphosphate dibasic, tricalcium phosphate, calcium carbonate, starch (suchas corn, maize, potato and rice starches), modified starches (such ascarboxymethyl starch, etc.), microcrystalline cellulose, sucrose,dextrose, maltodextrins, lactose, and fructose. The amount of binderadded to aggregate the particles into granules can be in the range offrom about 10% w/w to about 80% w/w including all values and rangestherebetween; and in certain embodiments is in the range of from about30% w/w to about 70% w/w of the powdered materials in the rotomeltgranulation. The remaining weight percentage to provide a total of about100% w/w can be one or more suitable powdered pharmaceutical actives.Optionally the rotomelt granulation can also contain from about 0% toabout 60% w/w including all values and ranges therebetween, of one ormore powdered excipients wherein the total weight of all the powderedmaterials equals about 100% w/w. The binder used in these embodiment ofthe invention can be a pharmaceutically acceptable dry powder haying aparticle size in the range of from about 5 μm to about 150 μm includingall values and ranges therebetween; and in certain embodiments in therange of from about 35 μm to about 80 μm. Suitable binders for rotomeltgranulation are low melting point powdered binders, examples of whichinclude: polyethylene glycol 4000, polyethylene glycol 6000, stearicacid, and low melting point waxes. Suitable low melting point waxesinclude but are not limited to glyceryl monostearate, hydrogenatedtallow, myristyl alcohol, myristic acid, stearyl alcohol, substitutedmonoglycerides, substituted diglycerides, substituted triglycerides,white beeswax, carnauba wax, castor wax, japan wax, acetylatemonoglycerides and combinations thereof. The binders can have a meltingpoint of from about 30° C. to about 100° C. including all values andranges therebetween; and in certain embodiments from about 40° C. toabout 85° C.

As a prophetic example of these embodiments that are manufactured by arotomelt granulation process, about 320g of bupropion hydrobromide andabout 80g PEG 8000 is dry blended and poured into a Glatt 1.1 chamberset-up as a rotary granulator with a longitudinal plate. Inlet airtemperature is set to about 60° C. and the product chamber heated toapproximately 50° C. The blend is fluidized at approximately 120 m3/hrand the frictional plate set to about 900 rpm. The product chambertemperature is raised to about 60° C. and then gradually reduced toabout 20° C. over a period of approximately 20 minutes, during whichspheronization is achieved.

Other embodiments of the invention involve the formation of amicroparticle that has a core which includes bupropion hydrobromide anda compound which is sweet in taste and which has a negative heat ofsolution. Examples of compounds falling into this category includemannitol and sorbitol. Sugars or artificial sweeteners to which, forexample, menthol have been added can also work as well. A binder and/orother excipient can also be disposed within the core. The amount ofsweetening compound used can depend on a number of factors including thesize of the resulting microparticles, the size or volume of theresulting tablet, the sturdiness of the microparticle-coatedmicroparticulant, the speed at which the tablet will disintegrate in themouth, the degree of sweetness imparted by the particular sweetenerused, either in the microparticle or in the tablet, or both, the amountof drug used, and the like. For example, particularly ruggedmicroparticles can be less likely to break during chewing and/orcompression. Therefore, the amount of material provided to protectagainst the release of objectionably flavored material can be lessened.In other cases a greater relative amount of sweetening compound can beused. Generally, the amount of sweetening material used will range fromgreater than zero to about 80% of the weight of the resultingmicroparticles including all values and ranges therebetween. Thesweetener and bupropion hydrobromide can be combined in any number ofknown ways, such as for example by wet granulation, dry granulation,agglomeration, or spray coating. For example, the sweetener can be usedas an adsorbent for the active agent. Alternatively, particles of eachcan also be simply mixed together. One or more binders, or otheradjuvants can also be used in the formulation of a tablet as well.Binders in these embodiments include, for example: starch (for example,in an amount of from about 5% to about 10% including all values andranges therebetween, as an aqueous paste); pregelatinized starch (forexample, in an amount of about 5% to about 10% including all values andranges therebetween, added dry to powder); gelatin (for example, in anamount of from about 2% to about 10% including all values and rangestherebetween, as an aquebus solution, or about 2% in starch paste);polyvinylpyrrolidone (for example, in an amount of from about 2% toabout 20% including all values and ranges therebetween, in an aqueous oralcoholic solution); methylcellulose (for example, in an amount of fromabout 2% to about 10% including all values and ranges therebetween, asan aqueous solution); sodium carboxy methylcellulose (for example, in anamount of from about 2% to about 10% including all values and rangestherebetween, as an aqueous solution); ethylcellulose (for example, inan amount of from about 5% to about 10% including all values and rangestherebetween, as an alcohol or hydroalcoholic solution); polyacrylamides(Polymer JR) (for example, in an amount of from about 2% to about 8%including all values and ranges therebetween, as an aqueous solution);polyvinyloxoazolidone (Devlex) (for example, in an amount of from about5% to about 10% including all values and ranges therebetween, as anaqueous or hydroalcoholic solution); and polyvinyl alcohols (forexample, in an amount of from about 5% to about 20% including all valuesand ranges therebetween, in aqueous solutions). Other adjuvants can alsobe used in forming the core of the microparticles of the presentembodiments of the invention, non-limiting examples of which include:calcium sulfate NF, Dibasic Calcium phosphate NF, Tribasic calciumsulfate NF, starch, calcium carbonate, microcrystalline cellulose,modified starches, lactose, sucrose and the like, STA-RXT™, AVICEL™,SOLKA-FLOC™ BW40, alginic acid, EXPLOTAB™, AUTOTAB™, guar gum, kaolinVECGUM™, and bentonite. These adjuvants can be used in up to about 20%w/w; and in certain embodiments are present in an amount of from about3% to about 5% w/w including all values and ranges therebetween.

As a prophetic example of these embodiments that have a core comprisingbupropion hydrobromide and a compound which is sweet in taste, bupropionhydrobromide can be granulated using the following procedure:Polyvinylpyrrolidone K-30 USP (about 240.0 gm) is dissolved intodistilled water (about 1,890.0 gm) with agitation. Mannitol powder USP(about 11,160 gm) and bupropion hydrobromide (about 600.0 gm) are placedin a Zanchetta 50-liter granulator/processor. After an initialtwo-minute dry mix of the powders with the chopper on and the propelleradjusted to about 200 rpm, the polyvinylpyrrolidone K-30 solution isslowly sprayed into the mixing powder bed using an air-driven spraysystem. The total time of granulation including the time of solutionaddition is approximately eight minutes. The granulation end-point isdetermined visually and by the consistency of the resulting material.The material is then discharged onto trays and dried at about 80° C.utilizing supplied dry air for a period of about six hours to a moisturecontent of not more than about 0.08 percent. The dried material is thenpassed through a hammermill (knives forward) equipped with a U.S. #40(420 micron) screen.

Other embodiments of this invention involve the combined granulation andcoating of bupropion hydrobromide into microparticles in which the drugis at least partly located within the microparticle core but capable ofimmediate release. To do this, the bupropion hydrobromide and a granulardisintegrant are first dry-mixed; the powder obtained is thengranulated, in the presence of a mixture of excipients comprising atleast one binder capable of binding the particles together to givegrains; the grains thus formed are then coated by spraying with asuspension comprising at least one coating agent and a membranedisintegrant; and then the coated granules obtained are dried. Thedistinction between the actual granulation and coating steps isrelatively theoretical, insofar as, even though the primary function ofthe binder used in the granulation step is to bind together theparticles, it nevertheless already partially coats the grains formed.Similarly, even though the primary function of the coating agent used inthe actual coating step is to complete the final coating of each of thegrains, it may, however, arbitrarily bind other coated grains by amechanism of granular agglomeration. The binder and the coating agentare chosen from the group comprising cellulose polymers and acrylicpolymers. However, even though the binder and the coating agent arechosen from the same group of compounds, they nevertheless differ fromeach other in their function as previously mentioned. Among thecellulose polymers that can be advantageously chosen are ethylcellulose,hydroxypropylcellulose (HPC), carboxymethylcellulose (CMC) andhydroxypropylmethylcel lu-lose (HPMC), or mixtures thereof. Among theacrylic polymers that can be advantageously chosen are theammonio-methacrylate copolymer (EUDRAGIT® RL or RS), the polyacrylate(EUDRAGIT® NE) and the methacrylic acid copolymer (EUDRAGIT® L or S). Inat least one embodiment, the binder is of the same nature as the coatingagent. To further accelerate the release of the bupropion hydrobromide,the coating suspension also comprises a permeabilizer which, on accountof its intrinsic solubility properties, causes perforation of themembrane coating, thus allowing the bupropion hydrobromide to bereleased. Non-limiting examples of permeabilizers include povidone andits derivatives, polyethylene glycol, silica, polyols and low-viscositycellulose polymers. Polymers of the type such as hypromellose, whoseviscosity is equal to about 6 centipoises, are used, for example, aslow-viscosity cellulose polymer. In at least one embodiment, thedry-mixing of initial powder and the granulation, coating and dryingsteps are performed in a fluidized bed. In this case, the initial powdermixture is first fluidized before being granulated by spraying saidpowder with the excipient mixture comprising at least the binder, thegrains obtained then being coated by spraying with the coatingsuspension, the coated granules formed finally being dried in thefluidized bed. In at least one embodiment, the mixture of excipientsused during the granulation step and the coating suspension used duringthe coating step form a single mixture. In this case, the granulationstep can be distinguished from the spraying step by varying differentparameters, such as the rate of spraying of the mixture and theatomization pressure of said mixture. Thus, only some of the mixture ofexcipients is used during the granulation step, while the other portioncan be used during the coating step.

Thus, the rate of spraying of the coating suspension is higher duringthe granulation step than during the coating step, whereas theatomization pressure of the coating suspension is lower during thegranulation step than during the coating step. In practice, at thelaboratory scale in a fluidized-bed device, for example of the type suchas Glatt GPCG1, during the granulation step, the rate of spraying of thecoating suspension is from about 10 grams/minute to about 25grams/minute including all values and ranges therebetween, and theatomization pressure is from about 1 bar to about 1.8 bar including allvalues and ranges therebetween. During the coating step, the rate ofspraying of the coating suspension is from about 5 grams/minute to about15 grams/minute including all values and ranges therebetween, while theatomization pressure is from about 1.5 bar to about 2.5 bar includingall values and ranges therebetween. In at least one embodiment, fromabout 10% to about 20% including all values and ranges therebetween, ofthe mixture of excipients is sprayed during the granulation step, theremainder being sprayed during the coating step.

As a prophetic example of these embodiments that involve the combinedgranulation and coating of bupropion hydrobromide into microparticles inwhich the drug is at least partly located within the microparticle corebut capable of immediate release, the microparticles can be manufacturedaccording to the following process: A granulation solution is firstprepared by dissolving about 48 g of ethylcellulose in about 273 g ofethyl alcohol. A coating suspension is then prepared by mixing about 97g of ethylcellulose, about 28.5 g of polyethylene glycol 6000, about 26g of sodium croscarmellose, about 10 g of precipitated silica and about27.5 g of aspartam in about 1900 g of ethyl alcohol, until a homogeneoussuspension is obtained. The powder mixture consisting of about 700 gramsof bupropion hydrobromide and about 35 grams of Acdisol is thenfluidized. The granulation is then started by spraying the granulationsolution for about 15 to about 20 minutes at a spraying rate of about 25grams/minute and a suspension atomization pressure of about 0.8 bar. Theactual coating is then performed by spraying the coating suspension forabout 1 hour 30 minutes at a spraying rate of about 15 to about 20grams/minute and a suspension spraying pressure of about 1.5 bar.

Other embodiments of the invention involve coating the bupropionhydrobromide material, thereby forming a drug-containing microparticle.One such process for achieving this involves:

Blending and fluidizing a powder mix of active principle and an adjuvantin order to obtain individual grains,Separately liquefying under warm conditions a lipid matrix agentcomprising either an ester of behenic acid and alcohol or an ester ofpalmitic/stearic acid and alcohol,Coating the fluidized powder mix under warm conditions by spraying thelipid matrix agent over the individual grains,Lowering the temperature of the combined product in order to allow thelipid matrix agent to solidify.

This process does not require an evaporation phase or a drying phase,since it does not require a wet-route or solvent-route granulation step,thus making it possible to be freed from any risk due to the presence oftoxic residues in the final product. Furthermore, it is not necessary tocarry out the quantitative determination of the traces of solvents, ananalysis that can be very expensive. According to the process of thisembodiment of the invention, the spraying conditions and thus thecoating characteristics can be modified, in order to vary the releaseprofile of bupropion hydrobromide, by varying several parameters, theadjustment characteristics of which remain simple. Thus, the sprayingair pressure can be increased in order to promote the formation of ahomogeneous film of lipid matrix agent around the grains.Advantageously, the rate of spraying of the lipid matrix agent cansimultaneously be decreased. In this case, the bupropion hydrobromiderelease profile, that is to say a percentage of dissolution as afunction of the time, is obtained which can be low, corresponding to aslow release of the drug. Conversely, the spraying air pressure can bedecreased in order to promote the agglomeration of the grains with oneanother. Advantageously, the rate of spraying of the lipid matrix agentcan simultaneously be increased. In this case, a release profile of thegrains obtained can be obtained which is high, corresponding to a rapidrelease of bupropion hydrobromide. In practice and according to the massof powder employed, the value of the rate of spraying of the lipidmatrix agent can be from two to four times higher when it is desired topromote the agglomeration of the grains with one another than when it isdesired to promote the formation of a homogeneous film around thegrains. On the other hand, the value of the spraying air pressure can befrom one to two times lower when it is desired to promote theagglomeration of the grains with one another than when it is desired topromote the formation of a homogeneous film around the grains. Accordingto the process for manufacturing these embodiments, it is possible,after having determined a given drug release profile, to vary the valuesof spraying air pressure and of spraying rate throughout the coatingstage, making it possible to promote the formation of a homogeneous filmaround the grains or to promote the agglomeration of the grains. Oncethe sequence of the duration of the spraying air pressure and of thespraying rate has been determined, the coating operation can be carriedout continuously and automatically. According to another characteristicof the process of manufacturing these embodiments, the temperature ofthe mixture of liquefied matrix agent and of spraying air is greater byabout 35° C. to about 60° C. than the melting temperature of the lipidmatrix agent. Likewise, the temperature of the fluidization air and thatof the powder is approximately equal to the melting temperature of thelipid matrix agent, plus or minus about 10° C. Furthermore, in order toobtain a mixture of individual grains, an air-operated fluidized beddevice or a turbine device can be used. Furthermore, the lipid matrixagent can be sprayed by the air spray technique, that is to say liquidspraying under pressure in the presence of compressed air. According toat least one embodiment, use is made of a powder comprising the drug andthe adjuvant. In other words, after mixing and fluidizing the combinedconstituents of the powder, the lipid matrix agent is sprayed over theindividual grains obtained. In order to avoid adhesion of the coatedgrains obtained, whether in the case where all the grains are treated orwhether in the case where only a portion of the grains is treated, astage of lubrication of the grains is inserted between the coating stageand the stage of putting into a pharmaceutical form. Furthermore, inorder to obtain greater stability of the pharmaceutical composition,that is to say in order to minimize modifications relating to therelease of the bupropion hydrobromide over time, the granules or tabletsobtained in certain embodiments of this example can be subjected to amaturing stage in an oven, for at least about 8 hours, at a temperatureof from about 45° C. to about 60° C.; and in certain embodiments atabout 55° C.

As a prophetic example of these drug-containing microparticleembodiments that are formed by coating the bupropion hydrobromidematerial, the drug-containing microparticles can be manufacturedaccording to the following process: A mixture of powder is preparedcomprising: bupropion hydrobromide; dicalcium phosphate dehydrate; andpolyvinylpyrrolidone. Batches of granules are prepared by a processcomprising the following stages: the mixture of powder obtained issieved; the said powder is mixed, heating while by means of anair-operated fluidized bed, in order to obtain individual grains; thelipid matrix agent (glyceryl behenate, e.g. COMPRITOL® 880 ATO) isliquefied separately at about 120° C.; the lipid matrix agent is sprayedover the heated powder mixture, and, finally, the temperature is loweredin order to allow the lipid matrix agent to solidify. These stages arecarried out while varying various parameters, either in order to promotethe formation of a homogeneous film around the grains or in order topromote the agglomeration of the grains, in accordance with thefollowing table:

Parameters Batch 1 Batch 2 Batch 3 Batch 4 % by weight of lipid matrixagent (COMPRITOL ® 888 ATO) 5 4 4 5 Fluidization air flow rate (m3/h) 80110 80 80 Agglomeration Atomization air pressure (bar) 2 1.5 1.5Temperature of the powder 70 70 74 bed (° C.) Spraying rate forCOMPRITOL ® 42 40 40 (g/min) Coating Atomization air pressure (bar) 2.53.5 2 2 Temperature of the powder 70 66 71 70 bed (° C.) Spraying ratefor COMPRITOL ® 41 20 40 40 (g/min)

Another embodiment of the invention for coating the bupropionhydrobromide material, thereby forming a drug-containing microparticle,involves the formation of coated microcrystals that can subsequently beincorporated into a tablet. Through selection of the appropriate polymerthe microcrystals can possess diversified features such asgastroresistance and controlled release due to the fact that the saidcoated or non-coated microcrystals and microgranules preserve, afterhaving been shaped in the form of a multiparticulate tablet, theirinitial properties amongst which are included masking of taste,gastroresistance and controlled release of the bupropion hydrobromide.In certain embodiments of this example, the following non-limiting listof polymers can be selected for coating of the bupropion hydrobromide inconventional fluidized based coating equipment: ethylcellulose (EC);hydroxypropylcellulose (HPC); hydroxypropylmethylcellulose (HPMC);gelatin; gelatin/acacia; gelatin/acacia/vinvylmethylether maleicanhydride; gelatin/acacia/ethylenemaleic anhydride; carboxymethylcellulose; polyvinvylalcohol; cellulose acetate phthalate;nitrocellulose; shellac; wax; polymethacrylate polymers such asEUDRAGIT® RS; EUDRAGIT® RL or combinations of both, EUDRAGIT® E andEUDRAGIT® NE30D; KOLLICOAT™ SR30D; and mixtures thereof.

Drug-Layered Microparticles

The drug-layered microparticles of certain embodiments can be made bycoating an inert particle or core, such as a non-pareil sphere (e.g.sugar sphere), with the bupropion hydrobromide salt and a polymericbinder. In certain embodiments of the drug-layered microparticles, theinert cores include water-insoluble materials such as cellulose spheresor silicon dioxide. In other embodiments, the inert cores includewater-soluble materials such as starch, salt or sugar spheres. The inertcores can have a diameter ranging from about 100 microns to about 2000microns including all values and ranges therebetween. For example, incertain embodiments the diameter of the inert cores range from about 150microns to about 1500 microns. In at least one embodiment, the inertcores are sugar spheres NF, containing not less than about 62.5% and notmore than about 91.5% of sucrose including all values and rangestherebetween. In at least one embodiment the inert cores havesubstantially consistent bulk density, low friability, and low dustgeneration properties. In at least one embodiment, the inert cores arecoated with an osmotic sub-coat comprising an osmotic agent and apolymeric binding agent. Further, the inert cores can initially becoated with a seal-coat to provide a more consistent core surface and tominimize any osmotic effects. The seal-coat layer can be applied to thecore prior to the application of the drug, polymeric binder, and anypolymeric film layers. In at least one embodiment, the seal-coat layerdoes not substantially modify the release of the bupropion hydrobromidesalt. Examples of suitable sealants that can be used in the seal-coatinclude permeable or soluble agents such as hydroxypropylmethylcellulose, hydroxypropyl cellulose, ethylcellulose, apolymethacrylate polymer, hydroxypropyl ethylcellulose, xanthan gum, andmixtures thereof. In at least one embodiment the sealant used in theseal-coat is hydroxypropyl methylcellulose. Other agents can be added toimprove the processability of the sealant. Examples of such agentsinclude talc, colloidal silica, polyvinyl alcohol, titanium dioxide,micronised silica, fumed silica, glycerol monostearate, magnesiumtrisilicate, magnesium stearate, and mixtures thereof. The seal-coatlayer can be applied from solution (e.g. aqueous) or suspension using afluidised bed coater (e.g. Wurster coating), or in a pan coating system.Examples of such seal-coats coatings are commercially available (e.g.OPADRY® White Y-1-7000 and OPADRY® OY/B/28920 White).

The binding agent of these drug-layered embodiments is used to adherethe bupropion hydrobromide salt layer to the inert core or seal-coat ofthe core. In certain embodiments, the binding agent is water soluble,possesses sufficiently high adhesivity in order to adhere the bupropionhydrobromide salt layer to the inert core, and possesses an appropriateviscosity to provide substantial adhesion between the inert core and thebupropion hydrobromide salt. In other embodiments the binding agent iswater-insoluble. In at least one embodiment the binding agent is ethylcellulose, a polymethacrylate polymer, polyvinylalcohol, polyvinylpyrrolidone, polyvinylpyrrolidone-vinylacetate copolymer (such asKOLLIDON® VA64), hydroxyethylcellulose, low molecular weighthydroxypropylmethylcellulose (e.g. viscosity of about 1-50 cps at about20° C.; about 2-12 cps at about 20° C.; or about 4-6 cps at about 20°C.), hydroxypropylcellulose polymethacrylates, or mixtures thereof. Forexample, in certain embodiments the composition of the binder forbupropion hydrobromide is from about 1% to about 25% w/w including allvalues and ranges therebetween; in other embodiments from about 2% toabout 10% w/w; and in still other embodiments from about 3% to about 5%w/w, expressed as a percentage of the total weight of the core.

Solvents can be used to apply the bupropion hydrobromide salt to theinert core, examples of which include lower alcohols such as ethanol,isopropanol and alcohol/water mixtures, acetone and chlorinatedhydrocarbons.

The drug-layered microparticles can be prepared by forming a suspensionor solution of the binder and the bupropion hydrobromide salt and thenlayering the suspension or solution on to the inert or sub-coated coreusing any of the layering techniques known in the art, such as fluidizedbed coating or pan coating. This can be affected in a single coating orthe process can be carried out in multiple layers, optionally withintervening drying/evaporation steps. This process can be conducted soas to produce microparticles containing a desired amount of bupropionhydrobromide salt and achieve the desired dosage and release thereofupon in-vivo administration.

In certain embodiments, the drug-layered microparticles can bemanufactured using for example, the procedure in the followinghypothetical experiment: Bupropion hydrobromide (about 2.8 kg) andhydroxypropyl methylcellulose (METHOCEL® E5) (about 0.40 kg) isdissolved in a mixture of water and isopropyl alcohol. The active drugsolution can then be sprayed onto sugar spheres 30/35 (about 1.06 kg) ina fluidized bed processor with a Wurster insert. The active coremicroparticles can then be dried in a fluidized bed processor until theloss on drying is below about 1%. The bupropion microparticles can thenbe passed through a 16 mesh screen and a 30 mesh screen andmicroparticles can be collected that are smaller than 16 mesh and largerthan 30 mesh.

Microparticle Taste-Masking Coatings

The microparticles of the present invention can each be coated with atleast one taste-masking coating. The taste-masking coating can mask thetaste of the active drug in the microparticles. In at least oneembodiment the taste-masking coating formulations contain polymericingredients. It is contemplated that other excipients consistent withthe objects of the present invention can also be used in thetaste-masking coating.

In at least one embodiment, the taste-masking coating comprises apolymer such as ethylcellulose, which can be used as a dry polymer (e.g.ETHOCEL®) solubilised in organic solvent prior to use, or as an aqueousdispersion. One commercially-available aqueous dispersion ofethylcellulose is AQUACOAT®. AQUACOAT® can be prepared by dissolving theethylcellulose in a water-immiscible organic solvent and thenemulsifying the same in water in the presence of a surfactant and astabilizer. After homogenization to generate submicron droplets, theorganic solvent is evaporated under vacuum to form a pseudolatex. Theplasticizer is not incorporated in the pseudolatex during themanufacturing phase. Thus, prior to using the same as a coating, theAQUACOAT® is intimately mixed with a suitable plasticizer prior to use.Another aqueous dispersion of ethylcellulose is commercially availableas SURELEASE®. This product can be prepared by incorporating plasticizerinto the dispersion during the manufacturing process. A hot melt of apolymer, plasticizer (e.g. dibutyl sebacate), and stabilizer (e.g. oleicacid) is prepared as a homogeneous mixture, which is then diluted withan alkaline solution to obtain an aqueous dispersion which can beapplied directly onto substrates.

In other embodiments, polymethacrylate acrylic polymers can be employedas taste masking polymers. In at least one embodiment, the taste maskingcoating is an acrylic resin lacquer used in the form of an aqueousdispersion (e.g. EUDRAGIT® or KOLLICOAT®). In further embodiments, theacrylic coating comprises a mixture of two acrylic resin lacquers (e.g.EUDRAGIT® RL and EUDRAGIT® RS, respectively).

EUDRAGIT® RL and EUDRAGIT® RS are copolymers of acrylic and methacrylicesters with a low content of quaternary ammonium groups, the molar ratioof ammonium groups to the remaining neutral (meth)acrylic esters being1:20 in EUDRAGIT® RL and 1:40 in EUDRAGIT® RS. The mean molecular weightis 150,000. The code designations RL (high permeability) and RS (lowpermeability) refer to the permeability properties of these agents.EUDRAGIT® RL/RS mixtures are insoluble in water and in digestive fluids.However, coatings formed from the same are swellable and permeable inaqueous solutions and digestive fluids. EUDRAGIT® RL/RS dispersions orsolutions of certain embodiments can be mixed together in any desiredratio in order to ultimately obtain a taste masking coating having adesirable drug dissolution profile. In certain embodiments formulationscan be obtained, for example, from a coating derived from 100% EUDRAGIT®RL; 50% EUDRAGIT® RL with 50% EUDRAGIT® RS; and 10% EUDRAGIT® RL with90% EUDRAGIT® RS.

In other embodiments, the taste masking polymer can be an acrylicpolymer which is cationic in character based on dimethylaminoethylmethacrylate and neutral methacrylic acid esters (e.g. EUDRAGIT® E). Thehydrophobic acrylic polymer coatings of the present invention canfurther include a neutral copolymer based on poly (meth)acrylates, suchas EUDRAGIT® NE. EUDRAGIT® NE 30D lacquer films are insoluble in waterand digestive fluids, but permeable and swellable.

In other embodiments, the taste masking polymer is a dispersion of poly(ethylacrylate, methyl methacrylate) 2:1 (KOLLICOAT® EMM 30 D, BASF).

In other embodiments, the taste masking polymer can be a polyvinylacetate stabilized with polyvinylpyrrolidone and sodium lauryl sulfatesuch as KOLLICOAT® SR30D (BASF).

Other taste masking polymers include hydroxypropylcellulose (HPC);hydroxypropylmethylcellulose (HPMC); hydroxyethylcellulose; gelatin;gelatin/acacia; gelatin/acacia/vinvylmethylether maleic anhydride;gelatin/acacia/ethylenemaleic anhydride; carboxymethyl cellulose;polyvinvylalcohol; nitrocellulose; polyvinylalcohol-polyethylene glycolgraft-copolymers; shellac; wax and mixtures thereof.

The taste-masking coatings can be applied to the microparticles from oneor more organic or aqueous solvent solutions or suspensions. In at leastone embodiment the organic solvents that can be used to apply thetaste-masking coatings include one or more of acetone, lower alcoholssuch as ethanol, isopropanol and alcohol/water mixtures, chlorinatedhydrocarbons, and the like. Devices used to coat the microparticles ofthe invention with a taste-masking coating include those conventionallyused in pharmaceutical processing, such as fluidized bed coatingdevices. The coatings applied to the microparticles can containingredients other than the functional polymers. One or more colorants,flavorants, sweeteners, can also be used in the taste-masking coating.

In some embodiments a pore former can be included into the taste maskingcoat in order to influence the rate of release of bupropion hydrobromidefrom the microparticle. In other embodiments, a pore former is notincluded in the taste masking coat. The pore formers can be inorganic ororganic, and include materials such as particulate materials that can bedissolved, extracted or leached from the coating in the environment ofuse. Upon exposure to fluids in the environment of use, the pore-formerscan for example be dissolved, and channels and pores are formed thatfill with the environmental fluid.

For example, the pore-formers of certain embodiments can comprise one ormore water-soluble hydrophilic polymers in order to modify the releasecharacteristics of the formulation. Examples of suitable hydrophilicpolymers used as pore-formers include hydroxypropylmethylcellulose,cellulose ethers and protein-derived materials of these polymers, thecellulose ethers, such as hydroxyalkylcelluloses andcarboxyalkylcelluloses. Also, synthetic water-soluble polymers can beused, examples of which include polyvinylpyrrolidone, cross-linkedpolyvinyl-pyrrolidone, polyethylene oxide, water-soluble polydextrose,saccharides and polysaccharides, such as pullulan, dextran, sucrose,glucose, fructose, mannitol, lactose, mannose, galactose, sorbitol andmixtures thereof. In at least one embodiment, the hydrophilic polymercomprises hydroxypropyl-methylcellulose.

Other non-limiting examples of pore-formers that can be used in certainembodiments containing a taste masking coat include alkali metal saltssuch as lithium carbonate, sodium chloride, sodium bromide, potassiumchloride, potassium sulfate, potassium phosphate, sodium acetate, sodiumcitrate and mixtures thereof. The pore-forming solids can also bepolymers which are soluble in the environment of use, such as CARBOWAX™,and CARBOPOL™. In addition, the pore-formers embrace diols, polyols,polyhydric alcohols, polyalkylene glycols, polyglycols,poly(a-w)alkylenediols and mixtures thereof. Other pore-formers whichcan be useful in the formulations of certain embodiments of the presentinvention include starch, modified starch, and starch derivatives, gums,including but not limited to xanthan gum, alginic acid, other alginates,benitoniite, veegum, agar, guar, locust bean gum, gum arabic, quincepsyllium, flax seed, okra gum, arabinoglactin, pectin, tragacanth,scleroglucan, dextran, amylose, amylopectin, dextrin, etc., cross-linkedpolyvinylpyrrolidone, ion-exchange resins, such as potassiumpolymethacrylate, carrageenan, kappa-carrageenan, lambdacarrageenan, gumkaraya, biosynthetic gum, and mixtures thereof. Other pore-formersinclude materials useful for making microporous lamina in theenvironment of use, such as polycarbonates comprised of linearpolyesters of carbonic acid in which carbonate groups reoccur in thepolymer chain, microporous materials such as bisphenol, a microporouspoly(vinylchloride), micro-porous polyamides, microporous modacryliccopolymers, microporous styrene-acrylic and its copolymers, porouspolysulfones, halogenated poly(vinylidene), polychloroethers, acetalpolymers, polyesters prepared by esterification of a dicarboxylic acidor anhydride with an alkylene polyol, poly(alkylenesulfides), phenolics,polyesters, asymmetric porous polymers, cross-linked olefin polymers,hydrophilic microporous hiomopolymers, copolymers or interpolymershaving a reduced bulk density, and other similar materials,poly(urethane), cross-linked chain-extended poly(urethane),poly(imides), poly(benzimidazoles), collodion, regenerated proteins,semi-solid cross-linked poly(vinylpyrrolidone), and mixtures thereof.

In general, the amount of pore-former included in the taste maskingcoatings of certain embodiments of the present invention can be fromabout 0.1% to about 80%, by weight including all values and rangestherebetween, relative to the combined weight of polymer andpore-former. The percentage of pore former as it relates to the dryweight of the taste-masking polymer, can have an influence on the drugrelease properties of the coated microparticle. In at least oneembodiment that uses water soluble pore formers such ashydroxypropylmethylcellulose, a taste masking polymer: pore former dryweight ratio of from about 10:1 to about 1:1 including all values andranges therebetween, can be present. In certain embodiments the tastemasking polymer: pore former dry weight ratio is from about 8:1 to about1.5:1; and in other embodiments from about 6:1 to about 2:1. In at leastone embodiment using EUDRAGIT® NE30D as the taste masking polymer and ahydroxypropylmethylcellulose (approx 5 cps viscosity (in a 2% aqueoussolution)) such as METHOCEL® E5, Pharmacoat 606G as the water solublepore former, a taste masking polymer: pore former dry weight ratio ofabout 2:1 is present.

Colorants that can be used in the taste-masking coating include food,drug and cosmetic colors (FD&C), drug and cosmetic colors (D&C) orexternal drug and cosmetic colors (Ext. D&C). These colors are dyes,lakes, and certain natural and derived colorants. Useful lakes includedyes absorbed on aluminum hydroxide or other suitable carriers.

Flavorants that can be used in the taste-masking coating include naturaland synthetic flavoring liquids. An illustrative list of such flavorantsincludes volatile oils, synthetic flavor oils, flavoring aromatics,oils, liquids, oleoresins and extracts derived from plants, leaves,flowers, fruits, stems and combinations thereof. A non-limitingrepresentative list of these includes citric oils, such as lemon,orange, grape, lime and grapefruit, and fruit essences, including apple,pear, peach, grape, strawberry, raspberry, cherry, plum, pineapple,apricot, or other fruit flavors. Other useful flavorants includealdehydes and esters, such as benzaldehyde (cherry, almond); citral,i.e., alpha-citral (lemon, lime); neral, i.e., beta-citral (lemon,lime); decanal (orange, lemon); aldehyde C-8 (citrus fruits); aldehydeC-9 (citrus fruits); aldehyde C-12 (citrus fruits); tolyl aldehyde(cherry, almond); 2,6-dimethyloctanal (green fruit); 2-dodenal (citrusmandarin); and mixtures thereof.

Sweeteners that can be used in the taste-masking coating include glucose(corn syrup), dextrose, invert sugar, fructose, and mixtures thereof(when not used as a carrier); saccharin and its various salts, such assodium salt; dipeptide sweeteners such as aspartame; dihydrochalconecompounds, glycyrrhizin; Steva Rebaudiana (Stevioside); chloroderivatives or sucrose such as sucralose; and sugar alcohols such assorbitol, mannitol, xylitol, and the like. Also contemplated arehydrogenated starch hydrolysates and the synthetic sweeteners such as3,6-dihydro-6-methyl-1-1-1,2,3-oxathiazin-4-1-2,2-dioxide, particularlythe potassium salt (acesulfame-K), and sodium and calcium salts thereof.The sweeteners can be used alone or in any combination thereof.

The microparticle taste masking coat can also include one or morepharmaceutically acceptable excipients such as lubricants, emulsifiers,anti-foaming agents, plasticizers, solvents and the like.

Lubricants can be included to help reduce friction of coatedmicroparticles during manufacturing. The lubricants that can be used inthe taste masking coat of the present invention include but are notlimited to adipic acid, magnesium stearate, calcium stearate, zincstearate, calcium silicate, magnesium silicate, hydrogenated vegetableoils, sodium chloride, sterotex, polyoxyethylene, glyceryl monostearate,talc, polyethylene glycol, sodium benzoate, sodium lauryl sulfate,magnesium lauryl sulfate, sodium stearyl fumarate, light mineral oil,waxy fatty acid esters such as glyceryl behenate, (i.e. COMPRITOL™),STEAR-O-WETT™, MYVATEX™ TL and mixtures thereof. In at least oneembodiment, the lubricant is selected from magnesium stearate, talc anda mixture thereof. Combinations of these lubricants are operable. Thelubricant can each be present in an amount of from about 1% to about100% by weight of the polymer dry weight in the taste masking coatincluding all values and ranges therebetween. For example, in certainembodiments wherein the taste masking polymer is EUDRAGIT® NE30D orEUDRAGIT® NE40D together with a hydrophilic pore former, the lubricantis present in an amount of from about 1% to about 30% by weight of thepolymer dry weight; in other embodiments from about 2% to about 20%; andin still other embodiments at about 10% by weight of the microparticletaste masking coat dry weight. In another embodiment where the tastemasking polymer is ethylcellulose (ETHOCEL™ PR100, PR45, PR20, PR10 orPR7 polymer, or a mixture thereof), the lubricant can be present in anamount of from about 10% to about 100% by weight of the microparticletaste masking coat dry weight; in another embodiment from about 20% toabout 80%; and in still another embodiments at about 50% by weight ofthe microparticle taste masking coat dry weight. In other embodiments,the taste masking coat does not include a pore former.

Emulsifying agent(s) (also called emulsifiers or emulgents) can beincluded in the microparticle taste masking coat to facilitate actualemulsification during manufacture of the coat, and also to ensureemulsion stability during the shelf-life of the product. Emulsifyingagents useful for the microparticle taste masking coat composition ofcertain embodiments include, but are not limited to naturally occurringmaterials and their semi synthetic derivatives, such as thepolysaccharides, as well as glycerol esters, cellulose ethers, sorbitanesters (e.g. sorbitan monooleate or SPAN™ 80), and polysorbates (e.g.TWEEN™ 80). Combinations of emulsifying agents are operable. In at leastone embodiment, the emulsifying agent is TWEEN™ 80. The emulsifyingagent(s) can be present in an amount of from about 0.01% to about 5% byweight of the microparticle taste masking polymer dry weight includingall values and ranges therebetween. For example, in certain embodimentsthe emulsifying agent is present in an amount of from about 0.05% toabout 3%; in other embodiments from about 0.08% to about 1.5%, and instill other embodiments at about 0.1% by weight of the microparticletaste masking polymer dry weight.

Anti-foaming agent(s) can be included in the microparticle taste maskingcoat to reduce frothing or foaming during manufacture of the coat.Anti-foaming agents useful for the coat composition include, but are notliminted to simethicone, polyglycol, silicon oil, and mixtures thereof.In at least one embodiment the anti-foaming agent is Simethicone C. Theanti-foaming agent can be present in an amount of from about 0.1% toabout 10% of the microparticle taste masking coat weight including allvalues and ranges therebetween. For example, in certain embodiments theanti-foaming agent is present in an amount of from about 0.2% to about5%; in other embodiments from about 0.3% to about 1%, and in still otherembodiments at about 0.6% by weight of the microparticle taste maskingpolymer dry weight.

Plasticizer(s) can be included in the microparticle taste masking coatto provide increased flexibility and durability during manufacturing.Plasticizers that can be used in the microparticle taste masking coat ofcertain embodiments include acetylated monoglycerides; acetyltributylcitrate, butyl phthalyl butyl glycolate; dibutyl tartrate; diethylphthalate; dimethyl phthalate; ethyl phthalyl ethyl glycolate; glycerin;propylene glycol; triacetin; tripropioin; diacetin; dibutyl phthalate;acetyl monoglyceride; acetyltriethyl citrate, polyethylene glycols;castor oil; rape seed oil, olive oil, sesame oil, triethyl citrate;polyhydric alcohols, glycerol, glycerin sorbitol, acetate esters,gylcerol triacetate, acetyl triethyl citrate, dibenzyl phthalate,dihexyl phthalate, butyl octyl phthalate, diisononyl phthalate, butyloctyl phthalate, dioctyl azelate, epoxidized tallate, triisoctyltrimellitate, diethylhexyl phthalate, di-n-octyl phthalate, di-i-octylphthalate, di-i-decyl phthalate, di-n-undecyl phthalate, di-n-tridecylphthalate, tri-2-ethylhexyl trimellitate, di-2-ethylhexyl adipate,di-2-ethylhexyl sebacate, di-2-ethylhexyl azelate, dibutyl sebacate,diethyloxalate, diethylmalate, diethylfumerate, dibutylsuccinate,diethylmalonate, dibutylphthalate, dibutylsebacate, glyceroltributyrate,and mixtures thereof. The plasticizer can be present in an amount offrom about 1% to about 80% of the taste masking polymer dry weightincluding all values and ranges therebetween. For example, in certainembodiments the plasticizer is present in an amount of from about 5% toabout 50%, in other embodiments from about 10% to about 40%, and instill other embodiments at about 20% of the taste masking polymer dryweight.

The taste-masking coating can be present in an amount of from about 1%to about 90% by weight of the microparticle including all values andranges therebetween, depending upon the choice of polymer, the ratio ofpolymer:pore former, and the total surface area of the microparticleformulation. Since a certain thickness of taste masking coating has tobe achieved in order to achieve effective taste masking, the amount oftaste masking polymer coating used during manufacture is related to thetotal surface area of the batch of uncoated microparticles that requiresa coating. The taste masking polymer surface area coverage can rangefrom about 0.5 mg/cm² to about 20 mg/cm² including all values and rangestherebetween. For example, in certain embodiments the surface areacoverage of the taste masking polymer is from about 0.6 mg/cm² to about10 mg/cm², and in other embodiments is from about 1 mg/cm² to about 5mg/cm². In at least one embodiment of the invention, EUDRAGIT® E isemployed as the taste masking polymer at a surface area coverage ofabout 4 mg/cm². One approach in estimating the total surface area of amultiparticulate batch is the permeability method according to Blaine(ASTM Des. C 205-55), which is based upon the mathematical model oflaminar flow through capillaries arranged in parallel.

In the absence of an accurate determination of total surface area of amicroparticle, the amount of taste masking polymer to be applied can beexpressed as a percentage of the uncoated microparticle. For example, incertain embodiments the taste-masking coating is present in an amount offrom about 5% to about 60% including all values and ranges therebetween;in other embodiments from about 10% to about 40%; and in still otherembodiments from about 15% to about 35% by weight of the microparticle.In at least one embodiment the taste-masking coating is present in anamount of about 30% by weight of the microparticle.

In certain embodiments, the diameter of the microparticles (with orwithout the taste-masking coating) range from about 50 μm to about 800μm including all values and ranges therebetween. For example, in certainembodiments the diameter of the microparticles range from about 100 μmto about 600 μm, and in other embodiments from about 150 μm to about 450μm.

Microparticle Controlled Release Coat

The microparticles of the present invention can each be coated with atleast one controlled release coat. As used herein, the term“microparticle controlled release coat” refers to the controlled releasecoat that substantially surrounds each microparticle. The microparticlecontrolled release coat is designed to achieve a controlled release ofthe bupropion hydrobromide salt from the microparticle. For example, themicroparticle controlled release coat can be an enteric coat with lowsolubility at a gastric pH to reduce or minimize the drug release in thelumen of the stomach, whilst possessing pH dependent solubility tofacilitate drug release in the duodenum. In another embodiment, thecontrolled release coat can be a delayed release coating that provides adelayed release of the bupropion hydrobromide salt with a predeterminedlagtime that is independent of, or alternatively dependent on, the pH ofthe dissolution medium. For example, by increasing the thickness of themicroparticle controlled release coat using a pH independent diffusionpolymer, lagtimes of about 1 hour, about 2 hours, about 3 hours, about 4hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about9 hours, about 10 hours, about 11 hours, or about 12 hours can beachieved. Alternatively, controlled release polymers can be selectedthat become soluble above a certain pH. Drug release from such a systemis reduced or minimized until the certain pH for the polymer of choiceis exceeded. With either approach, following the predetermined lag, drugis released, for example within about 1 hour for an immediate releasepulse, or alternatively over a prolonged period of time, for examplefrom about 3 to about 24 hours. In other embodiments, the microparticlecontrolled release coat can provide a diffusion barrier that isindependent of pH, thus facilitating a sustained release profile, withsubstantially full release of the bupropion hydrobromide salt occurringin from about 3 to about 24 hours following administration. In at leastone embodiment, the microparticle controlled release coat provides adelayed and sustained release of the bupropion hydrobromide salt fromthe microparticle with substantially full release in about 24 hoursfollowing administration.

In certain embodiments, the microparticle controlled release coat canprovide substantially full release of the bupropion hydrobromide saltfrom the microparticle without requiring the use of any pore formers.Unnecessary pore formers that are not required in the microparticlecontrolled release coat include hydrophilic polymers such ashydroxypropyl methylcellulose.

The microparticle controlled release coat includes at least one polymerin an amount sufficient to achieve a controlled release of the bupropionhydrobromide salt. In at least one embodiment of the invention thecontrolled release polymer is an acrylic polymer. Suitable acrylicpolymers include but are not limited to acrylic acid and methacrylicacid copolymers, methyl methacrylate copolymers, ethoxyethylmethacrylates, cynaoethyl methacrylate, aminoalkyl methacrylatecopolymer, poly(acrylic acid), poly(methacrylic acid, methacrylic acidalkylamine copolymer, poly(methyl methacrylate), poly(methacrylic acid)(anhydride), glycidyl methacrylate copolymers, and mixtures thereof.

In at least one embodiment the controlled release coat comprisespolymerizable quaternary ammonium compounds, of which non-limitingexamples include quaternized aminoalkyl esters and aminoalkyl amides ofacrylic acid and methacrylic acid, for exampleβ-methacryl-oxyethyl-trimethyl-ammonium methosulfate,β-acryloxy-propyl-trimethyl-ammonium chloride,trimethylaminomethyl-methacrylamide methosulfate and mixtures thereof.The quaternary ammonium atom can also be part of a heterocycle, as inmethacryloxyethylmethyl-morpholiniom chloride or the correspondingpiperidinium salt, or it can be joined to an acrylic acid group or amethacrylic acid group by way of a group containing hetero atoms, suchas a polyglycol ether group. Further suitable polymerizable quaternaryammonium compounds include quaternized vinyl-substituted nitrogenheterocycles such as methyl-vinyl pyridinium salts, vinyl esters ofquaternized amino carboxylic acids, and styryltrialkyl ammonium salts.Other polymerizable quaternary ammonium compounds useful in the presentinvention include acryl- and methacryl-oxyethyltrimethyl-ammoniumchloride and methosulfate, benzyldimethylammoniumethyl-methacrylatechloride, diethylmethylammoniumethyl-acrylate and -methacrylatemethosulfate, N-trimethylammoniumpropylmethacrylamide chloride,N-trimethylammonium-2,2-dimethylpropyl-1-methacrylate chloride andmixtures thereof.

In at least one embodiment, the polymer of the controlled release coatis an acrylic polymer comprised of one or more ammonio methacrylatecopolymers. Ammonio methacrylate copolymers (e.g. EUDRAGIT® RS and RL)are described in NF XVII as fully polymerized copolymers of acrylic andmethacrylic acid esters with a low content of quaternary ammoniumgroups. In order to obtain a desirable dissolution profile for a giventherapeutically active agent such as bupropion hydrobromide, it may behelpful in some embodiments to incorporate two or more ammoniomethacrylate copolymers having differing physical properties. Forexample, it is known that by changing the molar ratio of the quaternaryammonium groups to the neutral (meth)acrylic esters, the permeabilityproperties of the resultant controlled release coat can be modified.

In other embodiments of the present invention, the acrylic polymercoating further includes a polymer whose permeability is pH dependent,such as anionic polymers synthesized from methacrylic acid andmethacrylic acid methyl ester (e.g. EUDRAGIT® L and EUDRAGIT® S).EUDRAGIT® L is insoluble in acids and pure water, but becomesincreasingly permeable above pH 5.0. EUDRAGIT® S is similar, except thatit becomes increasingly permeable above pH 7. The hydrophobic acrylicpolymer coatings can also include a polymer which is cationic incharacter based on dimethylaminoethyl methacrylate and neutralmethacrylic acid esters (e.g. EUDRAGIT® E). The hydrophobic acrylicpolymer coatings of certain embodiments can further include a neutralcopolymer based on poly (meth)acrylates, such as EUDRAGIT® NE

In other embodiments of the invention the controlled release polymer isa dispersion of poly (ethylacrylate, methyl methacrylate) 2:1 (e.g.KOLLICOAT® EMM 30 D). In other embodiments the controlled releasepolymer can be a polyvinyl acetate stabilized with polyvinylpyrrolidoneand sodium lauryl sulfate such as KOLLICOAT® SR30D. The dissolutionprofile can be altered by changing the relative amounts of differentacrylic resin lacquers included in the coating. Also, by changing themolar ratio of polymerizable permeability-enhancing agent (e.g., thequaternary ammonium compounds) in certain embodiments to the neutral(meth)acrylic esters, the permeability properties (and thus thedissolution profile) of the resultant coating can be modified.

In at least one embodiment the controlled release polymer isethylcellulose, which can be used as a dry polymer (e.g. ETHOCEL®)solubilised in organic solvent prior to use, or as an aqueousdispersion. One commercially available aqueous dispersion ofethylcellulose is AQUACOAT®. AQUACOAT® can be prepared by dissolving theethylcellulose in a water-immiscible organic solvent and thenemulsifying the same in water in the presence of a surfactant and astabilizer. After homogenization to generate submicron droplets, theorganic solvent is evaporated under vacuum to form a pseudolatex. Theplasticizer is not incorporated in the pseudolatex during themanufacturing phase. Thus, prior to using the same as a coating, theAQUACOAT® is intimately mixed with a suitable plasticizer prior to use.Another aqueous dispersion of ethylcellulose is SURELEASE®. This productcan be prepared by incorporating a plasticizer into the dispersionduring the manufacturing process. A hot melt of a polymer, plasticizer(e.g. dibutyl sebacate), and stabilizer (e.g. oleic acid) is prepared asa homogeneous mixture, which is then diluted with an alkaline solutionto obtain an aqueous dispersion which can be applied directly ontosubstrates.

Other examples of polymers that can be used in the microparticlecontrolled release coat include cellulose acetate phthalate, celluloseacetate trimaletate, hydroxy propyl methylcellulose phthalate, polyvinylacetate phthalate, polyvinyl alcohol phthalate, shellac; hydrogels andgel-forming materials, such as carboxyvinyl polymers, sodium alginate,sodium carmellose, calcium carmellose, sodium carboxymethyl starch, polyvinyl alcohol, hydroxyethyl cellulose, methyl cellulose, ethylcellulose, gelatin, starch, and cellulose based cross-linked polymers inwhich the degree of crosslinking is low so as to facilitate adsorptionof water and expansion of the polymer matrix, hydroxypropyl cellulose,hydroxypropyl methylcellulose, polyvinylpyrrolidone, crosslinked starch,microcrystalline cellulose, chitin, pullulan, collagen, casein, agar,gum arabic, sodium carboxymethyl cellulose, (swellable hydrophilicpolymers) poly(hydroxyalkyl methacrylate) (molecular weight from about5k to about 5000k), polyvinylpyrrolidone (molecular weight from about10k to about 360k), anionic and cationic hydrogels, zein, polyamides,polyvinyl alcohol having a low acetate residual, a swellable mixture ofagar and carboxymethyl cellulose, copolymers of maleic anhydride andstyrene, ethylene, propylene or isobutylene, pectin (molecular weightfrom about 30k to about 300k), polysaccharides such as agar, acacia,karaya, tragacanth, algins and guar, polyacrylamides, POLYOX®polyethylene oxides (molecular weight from about 100k to about 5000k),AQUAKEEP® acrylate polymers, diesters of polyglucan, crosslinkedpolyvinyl alcohol and poly N-vinyl-2-pyrrolidone, hydrophilic polymerssuch as polysaccharides, methyl cellulose, sodium or calciumcarboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropylcellulose, hydroxyethyl cellulose, nitro cellulose, carboxymethylcellulose, cellulose ethers, methyl ethyl cellulose, ethylhydroxyethylcellulose, cellulose acetate, cellulose butyrate, cellulosepropionate, gelatin, starch, maltodextrin, pullulan, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerol fatty acidesters, polyacrylamide, polyacrylic acid, natural gums, lecithins,pectin, alginates, ammonia alginate, sodium, calcium, potassiumalginates, propylene glycol alginate, agar, and gums such as arabic,karaya, locust bean, tragacanth, carrageens, guar, xanthan, scleroglucanand mixtures and blends thereof.

In at least one embodiment the controlled release coat of themicroparticles comprises polymers that can facilitate mucoadhsion withinthe gastrointestinal tract. Non-limiting examples of polymers that canbe used for mucoadhesion include carboxymethylcellulose, polyacrylicacid, CARBOPOL™, POLYCARBOPHIL™, gelatin and other natural or syntheticpolymers.

In at least one embodiment the microparticles are coated with acontrolled release coat comprised of: at least one film-forming polymerwhich is insoluble in the liquids of the digestive tract, present in anamount of from about 50% to about 90% including all values and rangestherebetween (e.g. from about 50% to about 80%) by weight of dry matterof the controlled release coat composition, and including at least onenon-hydrosoluble cellulose derivate, (e.g. ethylcellulose, celluloseacetate, or mixtures thereof); at least one nitrogen-containing polymer,present in an amount of from about 2% to about 25% including all valuesand ranges therebetween (e.g. from about 5% to about 15%) by weight ofdry matter of the controlled release coat composition, and including atleast one polyacrylamide, poly-N-vinylaride, poly-N-vinyl-lactame,polyvinylpyrrolidone, or mixtures thereof; optionally a plasticizerpresent in an amount of from about 2% to about 20% including all valuesand ranges therebetween (e.g. from about 4% to about 15%) by weight ofdry matter of the controlled release coat composition, and including atleast one of the following compounds: glycerol esters, phtalates,citrates, sebacates, cetylalcohol esters, castor oil, cutin, or mixturesthereof; at least one surface-active and/or lubricating agent, presentin an amount of from about 2% to about 20% including all values andranges therebetween (e.g. from about 4% to about 15%) by weight of drymatter of the controlled release coat composition, and chosen fromanionic surfactants such as the alkali metal and alkakine-earth metalsalts of fatty acids, (e.g. stearic acid, oleic acid, and mixturesthereof), and/or from nonionic surfactants such as polyoxyethylenatedesters of sorbitan, polyoxyethylenated esters of sorbitan,polyoxyethylenated derivatives of castor oil, and/or from lubricantssuch as stearates (e.g. calcium, magnesium, aluminium, zinc stearate andmixtures thereof), stearylfumarates (e.g. sodium stearylfumarate,glyceryl behenate and mixtures thereof); and mixtures thereof; whereinthe coated microparticles are designed so as to be able to remain in thesmall intestine for a period of at least about 5 hours; in certainembodiments at least about 7 hours; and in certain other embodiments fora period of from about 8 hours to about 24 hours; so as to allowabsorption of the bupropion hydrobromide during at least part of itstime in the small intestine.

In a prophetic example of this embodiment of the invention, themicroparticles are coated in a fluidized bead coater with the followingcoating solution:

Ethylcellulose about 44.7 g PVP about 4.8 g Castor oil about 4.8 gMagnesium Stearate about 6.1 g Acetone about 479 g Isopranol about 53 g

In other embodiments of the present invention, the release of thebupropion hydrobromide from a controlled release formulation can befurther influenced, i.e., adjusted to a desired rate, by the addition ofone or more pore-formers to the controlled release coat, where thepore-formers can be inorganic or organic, and can include materials thatcan be dissolved, extracted or leached from the controlled release coatin the environment of use. Upon exposure to fluids in the environment ofuse, the pore-formers are, for example, dissolved, and channels andpores are formed that fill with the environmental fluid. For example,the pore-formers can include one or more water-soluble hydrophilicpolymers in order to modify the release characteristics of theformulation. Non-limiting examples of suitable hydrophilic polymersinclude hydroxypropylmethylcellulose, cellulose ethers andprotein-derived materials of these polymers, the cellulose ethers, (e.g.hydroxyalkylcelluloses and carboxyalkylcelluloses), and mixturesthereof. Also, synthetic water-soluble polymers can be used, such aspolyvinylpyrrolidone, cross-linked polyvinyl-pyrrolidone, polyethyleneoxide, water-soluble polydextrose, saccharides and polysaccharides, suchas pullulan, dextran, sucrose, glucose, fructose, mannitol, lactose,mannose, galactose, sorbitol, and mixtures thereof. In at least oneembodiment the hydrophilic polymer(s) includehydroxypropyl-methylcellulose. Other examples of pore-formers includealkali metal salts such as lithium carbonate, sodium chloride, sodiumbromide, potassium chloride, potassium sulfate, potassium phosphate,sodium acetate, sodium citrate, and mixtures thereof. The pore-formingsolids can also be polymers which are soluble in the environment of use,such as CARBOWAX®, CARBOPOL®, and the like. The possible pore-formersembrace diols, polyols, polyhydric alcohols, polyalkylene glycols,polyglycols, poly(a-w)alkylenediols, and mixtures thereof. Otherpore-formers which can be useful in the formulations of the presentinvention include starch, modified starch, and starch derivatives, gums,including but not limited to xanthan gum, alginic acid, other alginates,benitoniite, veegum, agar, guar, locust bean gum, gum arabic, quincepsyllium, flax seed, okra gum, arabinoglactin, pectin, tragacanth,scleroglucan, dextran, amylose, amylopectin, dextrin, etc., cross-linkedpolyvinylpyrrolidone, ion-exchange resins, such as potassiumpolymethacrylate, carrageenan, kappa-carrageenan, lambda-carrageenan,gum karaya, biosynthetic gum, and mixtures thereof. Other pore-formersinclude materials useful for making microporous lamina in theenvironment of use, such as polycarbonates comprised of linearpolyesters of carbonic acid in which carbonate groups reoccur in thepolymer chain, microporous materials such as bisphenol, a microporouspoly(vinylchloride), micro-porous polyamides, microporous modacryliccopolymers, microporous styrene-acrylic and its copolymers, porouspolysulfones, halogenated poly(vinylidene), polychloroethers, acetalpolymers, polyesters prepared by esterification of a dicarboxylic acidor anhydride with an alkylene polyol, poly(alkylenesulfides), phenolics,polyesters, asymmetric porous polymers, cross-linked olefin polymers,hydrophilic microporous hiomopolymers, copolymers or interpolymershaving a reduced bulk density, and other similar materials,poly(urethane), cross-linked chain-extended poly(urethane),poly(imides), poly(benzimidazoles), collodion, regenerated proteins,semi-solid cross-linked poly(vinylpyrrolidone), and mixtures thereof.

In other embodiments a surfactant or an effervescent base can beincluded in the controlled release coat, which can reduce and in certainembodiments overcome surface tension effects. In addition, thecontrolled release coat of certain embodiments can include one or moreosmagents (i.e., which can osmotically deliver the active agent from thedevice by providing an osmotic pressure gradient against the externalfluid), swelling agents (i.e., which can include, but are not limited tohydrophilic pharmaceutically acceptable compounds with various swellingrates in water), or other pharmaceutically acceptable agents (i.e.,provided in an amount sufficient to facilitate the entry of theenvironmental fluid without causing the disruption of the impermeablecoating). The surfactants that can be used in the controlled releasecoat of certain embodiments can be anionic, cationic, nonionic, oramphoteric. Non-limiting examples of such surfactants include sodiumlauryl sulfate, sodium dodecyl sulfate, sorbitan esters, polysorbates,pluronics, potassium laurate, and mixtures thereof. Non-limitingexamples of effervescent bases that can be used in the controlledrelease coat of certain embodiments include sodium glycine carbonate,sodium carbonate, potassium carbonate, sodium bicarbonate, potassiumbicarbonate, calcium bicarbonate, and mixtures thereof. Non-limitingexamples of osmagents that can be used in the controlled release coat ofcertain embodiments include sodium chloride, calcium chloride, calciumlactate, sodium sulfate, lactose, glucose, sucrose, mannitol, urea,other organic and inorganic compounds known in the art, and mixturesthereof. The swelling agent can include, but is not limited to at leastone pharmaceutically acceptable hydrophilic compound, having a swellingrate or swelling amount in water at about 25° C. that is: greater thanor equal to at least about 10% by weight (wt/wt), greater than or equalto at least about 15% by weight (wt/wt), or greater than or equal to atleast about 20% by weight (wt/wt). Non-limiting examples of swellingagents that can be used in the controlled release coat of certainembodiments of the present invention include crosslinkedpolyvinylpyrrolidones (e.g. polyplasdone, crospovidone and mixturesthereof), crosslinked carboxyalkylcelluloses, crosslinkedcarboxymethylcellulose (e.g. crosslinked sodium croscarmellose),hydrophilic polymers of high molar mass (i.e., which can be, but are notlimited to being greater than or equal to 100,000 Daltons) which caninclude, but are not limited to: polyvinylpyrrolidone(s), polyalkyleneoxides (e.g. polyethylene oxide, polypropylene oxide, and mixturesthereof), hydroxyalkylcelluloses (e.g. hydroxypropylcellulose,hydroxypropylmethylcellulose and mixtures thereof),carboxyalkylcellulose (e.g. carboxymethylcellulose), modified starch(e.g. sodium glycolate), starch or natural starch (e.g. corn, wheat,rice, potato and mixtures thereof), cellulose (i.e. which can be, but isnot limited to being in powder form or microcrystalline form), sodiumalginate, potassium polacriline, and corresponding blends or mixturesthereof. In other embodiments, non-limiting examples of the swellingagent include the following sub-set of compounds: crosslinkedpolyvinylpyrrolidone (e.g. polyplasdone, crospovidone or mixturesthereof), crosslinked carboxyalkylcelluloses (e.g. crosslinkedcarboxymethylcelluloses such as crosslinked sodium croscarmellose), andmixtures thereof. In other embodiments, the swelling agent can be anitrogen containing polymer, non-limiting examples of which can includepolyvinylpyrrolidone, crosslinked polyvinylpyrrolidone and mixturesthereof. The concentration of the swelling agent in the controlledrelease coat of certain embodiments of the present invention can be fromabout 3% to about 40% by weight of the microparticle including allvalues and ranges therebetween. For example, in certain embodiments theconcentration of the swelling agent in the controlled release coat isfrom about 4% to about 30%, and in other embodiments from about 5% toabout 25% by weight of the microparticle.

In certain embodiments one or more pharmaceutically acceptableexcipients consistent with the objects of the present invention can beused in the controlled release coat, such as a lubricant, an emulsifyingagent, an anti-foaming agent, and/or a plasticizer.

Lubricants can be included in the controlled release coat to help reducefriction of coated microparticles during manufacturing. The lubricantsthat can be used in the controlled release coat of certain embodimentsof the present invention include but are not limited to adipic acid,magnesium stearate, calcium stearate, zinc stearate, calcium silicate,magnesium silicate, hydrogenated vegetable oils, sodium chloride,sterotex, polyoxyethylene, glyceryl monostearate, talc, polyethyleneglycol, sodium benzoate, sodium lauryl sulfate, magnesium laurylsulfate, sodium stearyl fumarate, light mineral oil, waxy fatty acidesters such as glyceryl behenate, (e.g. COMPRITOL™), STEAR-O-WET™ andMYVATEX™ TL. In at least one embodiment, the lubricant is selected frommagnesium stearate, talc and mixtures thereof. Combinations of theselubricants are operable. The lubricant can each be present in an amountof from about 1% to about 100% by weight of the controlled release coatdry weight including all values and ranges therebetween. For example, incertain embodiments wherein the controlled release polymer is EUDRAGIT®NE30D or EUDRAGIT® NE40D together with a hydrophilic pore former, thelubricant is present in an amount of from about 1% to about 30% byweight of the controlled release coat dry weight; in other embodimentsfrom about 2% to about 20%; and in still other embodiments at about 10%by weight of the microparticle controlled release coat dry weight. Inanother embodiments where the controlled release polymer isethylcellulose (ETHOCEL™ PR100, PR45, PR20, PR10 or PR7 polymer, or amixture thereof), the lubricant can be present in an amount of fromabout 10% to about 100% by weight of the microparticle control-releasingcoat dry weight; in another embodiment from about 20% to about 80%; andin still another embodiments at about 50% by weight of the microparticlecontrol-releasing coat dry weight.

Emulsifying agent(s) (also called emulsifiers or emulgents) can beincluded in the microparticle controlled release coat to facilitateactual emulsification during manufacture of the coat, and also to ensureemulsion stability during the shelf-life of the product. Emulsifyingagents useful for the microparticle control-releasing coat compositioninclude, but are not limited to naturally occurring materials and theirsemi synthetic derivatives, such as the polysaccharides, as well asglycerol esters, cellulose ethers, sorbitan esters (e.g. sorbitanmonooleate or SPAN™ 80), and polysorbates (e.g. TWEEN™ 80). Combinationsof emulsifying agents are operable. In at least one embodiment, theemulsifying agent is TWEEN™ 80. The emulsifying agent(s) can be presentin an amount of from about 0.01% to about 5% by weight of themicroparticle controlled release coat dry weight including all valuesand ranges therebetween. For example, in certain embodiments theemulsifying agent is present in an amount of from about 0.05% to about3%; in other embodiments from about 0.08% to about 1.5%, and in stillother embodiments at about 0.1% by weight of the microparticlecontrolled release coat dry weight.

Anti-foaming agent(s) can be included in the microparticle controlledrelease coat to reduce frothing or foaming during manufacture of thecoat. Anti-foaming agents useful for the coat composition include, butare not liminted to simethicone, polyglycol and silicon oil. In at leastone embodiment the anti-foaming agent is Simethicone C. The anti-foamingagent can be present in an amount of from about 0.1% to about 10% of themicroparticle controlled release coat weight including all values andranges therebetween. For example, in certain embodiments theanti-foaming agent is present in an amount of from about 0.2% to about5%; in other embodiments from about 0.3% to about 1%, and in still otherembodiments at about 0.6% by weight of the microparticle controlledrelease coat dry weight.

Plasticizer(s) can be included in the microparticle controlled releasecoat to modify the properties and characteristics of the polymers usedin the coat for convenient processing during manufacturing (e.g. provideincreased flexibility and durability during manufacturing). As usedherein, the term “plasticizer” includes any compounds capable ofplasticizing or softening a polymer or binder used in the presentinvention. Once the coat has been manufactured, certain plasticizers canfunction to increase the hydrophilicity of the coat in the environmentof use. During manufacture of the coat, the plasticizer can lower themelting temperature or glass transition temperature (softening pointtemperature) of the polymer or binder. The addition of a plasticizer,such as low molecular weight PEG, generally broadens the averagemolecular weight of a polymer in which they are included therebylowering its glass transition temperature or softening point.Plasticizers can also generally reduce the viscosity of a polymer.Non-limiting examples of plasticisers that can be used in themicroparticle controlled release coat include acetylated monoglycerides;acetyltributyl citrate, butyl phthalyl butyl glycolate; dibutyltartrate; diethyl phthalate; dimethyl phthalate; ethyl phthalyl ethylglycolate; glycerin; propylene glycol; triacetin; tripropioin; diacetin;dibutyl phthalate; acetyl monoglyceride; acetyltriethyl citrate,polyethylene glycols; castor oil; rape seed oil, olive oil, sesame oil,triethyl citrate; polyhydric alcohols, glycerol, glycerin sorbitol,acetate esters, gylcerol triacetate, acetyl triethyl citrate, dibenzylphthalate, dihexyl phthalate, butyl octyl phthalate, diisononylphthalate, butyl octyl phthalate, dioctyl azelate, epoxidized tallate,triisoctyl trimellitate, diethylhexyl phthalate, di-n-octyl phthalate,di-i-octyl phthalate, di-i-decyl phthalate, di-n-undecyl phthalate,di-n-tridecyl phthalate, tri-2-ethylhexyl trimellitate, di-2-ethylhexyladipate, di-2-ethylhexyl sebacate, di-2-ethylhexyl azelate, dibutylsebacate, diethyloxalate, diethylmalate, diethylfumerate,dibutylsuccinate, diethylmalonate, dibutylphthalate, dibutylsebacate,glyceroltributyrate, and mixtures thereof. The plasticizer can bepresent in an amount of from about 1% to about 80% of the controlledrelease coat dry weight including all values and ranges therebetween.For example, in certain embodiments the plasticizer is present in anamount of from about 5% to about 50%, in other embodiments from about10% to about 40%, and in still other embodiments at about 20% of thecontrolled release coat dry weight.

The controlled release coat can be present in an amount of from about 1%to about 100% by weight of the microparticle including all values andranges therebetween, depending upon the choice of polymer, the ratio ofpolymer:pore former, and the total surface area of the microparticleformulation. Since a certain thickness of controlled release coating hasto be achieved in order to achieve the desired dissolution profile, theamount of polymer coating required during manufacture is related to thetotal surface area of the batch of uncoated microparticles that requiresa coating. The controlled release polymer surface area coverage canrange from about 0.5 mg/cm² to about 30 mg/cm² including all values andranges therebetween. For example in certain embodiments the surface areacoverage of the controlled release polymer is from about 0.6 mg/cm² toabout 20 mg/cm², and in other embodiments from about 1 mg/cm² to about 5mg/cm². In at least one embodiment of the invention, EUDRAGIT® NE30D isused as the controlled release polymer at a surface area coverage ofabout 10 mg/cm². One approach to estimate the total surface area of amultiparticulate batch is the permeability method according to Blaine(ASTM Des. C 205-55), which is based upon the mathematical model oflaminar flow through capillaries arranged in parallel. In the absence ofan accuracte determination of total surface area of a microoparticle,the amount of controlled release polymer to be applied can be expressedas a percentage of the uncoated microparticle.

The controlled release polymer can be present in an amount of from about1% to about 99% by weight of the coated microparticle including allvalues and ranges therebetween, depending on the controlled releaseprofile desired. For example, in certain embodiments the polymer ispresent in an amount of from about 5% to about 80%, and in otherembodiments from about 10% to about 50% by weight of the coatedmicroparticle. In at least one embodiment wherein the controlled releasepolymer is EUDRAGIT® NE30D, EUDRAGIT® NE40D, KOLLICOAT® SR 30D, or amixture thereof, the polymer is present in an amount of from about 1% toabout 50%; in other embodiments from about 5% to about 30%; and in stillother embodiments is about 15% by weight of the coated microparticle. Inat least one embodiment wherein the controlled release polymer isethylcellulose, the polymer is present in an amount of from about 1% toabout 99% by weight of the coated microparticle; in other embodimentsfrom about 5% to about 50%; and in still other embodiments at about 20%by weight of the coated microparticle. In at least one embodimentwherein the controlled release polymer is ETHOCEL™, an ethyl cellulosegrade PR100, PR45, PR20, PR10, PR7 polymer, or a mixture thereof, thepolymer is present in an amount of from about 5% to about 30% by weightof the coated microparticle; in other embodiments from about 10% toabout 25%; and in still other embodiments at about 20% by weight of thecoated microparticle.

In certain embodiments, the diameter of the microparticles (with orwithout the controlled release coat) can range from about 50 μm to about800 μm including all values and ranges therebetween. For example, incertain embodiments the diameter of the microparticles range from about100 μm to about 600 μm, and in other embodiments from about 150 μm toabout 450 μm.

It is contemplated that in alternative embodiments, other excipientsconsistent with the objects of the present invention can also be used inthe microparticle controlled release coat.

In at least one embodiment, the microparticle controlled release coatincludes about 96% EUDRAGIT® NE30D, about 1.9% Magnesium stearate, about1.9% Talc, about 0.04% TWEEN® 80, and about 0.19% Simethicone C, whenexpressed as percentage by weight of the dry controlled release coatcomposition. In another embodiment, the microparticle controlled releasecoat includes about 68% ethylcellulose, about 17% glyceryl monostearateand about 15% acetyl tributylcitrate when expressed as percentage byweight of the dry controlled release coat composition.

In certain embodiments the microparticle controlled release coat can bemade according to any one of the methods described herein.

The manufacturing process for the microparticle controlled release coatcan be as follows. Water is split into two portions of about 15% andabout 85%. The anti-foaming agent and the emulsifying agent are thenadded to the 15% water portion, and mixed at about 300 rpm to formportion A. In at least one embodiment, the anti-foaming agent isSimethicone C, and the emulsifying agent is TWEEM™ 80. A first lubricantis then added to the 85% water portion and mixed at about 9500 rpm toform portion B. In at least one embodiment, the first lubricant is talc.Then portion A is mixed with portion B, a second lubricant is slowlyadded, and mixed at about 700 rpm overnight. In at least one embodiment,the second lubricant is magnesium stearate. Finally, an aqueousdispersion of a neutral ester copolymer is added and mixed for about 30minutes at about 500 rpm. In at least one embodiment, the aqueousdispersion of a neutral ester copolymer is EUDRAGIT® NE30D. Theresultant controlled release coat solution can then be used to coat themicroparticles to about a 35% weight gain with the following parameters:An inlet temperature of from about 10° C. to about 60° C. including allvalues and ranges therebetween, in certain embodiments from about 20° C.to about 40° C., and in at least one embodiment from about 25° C. toabout 35° C.; an outlet temperature of from about 10° C. to about 60° C.including all values and ranges therebetween, in certain embodimentsfrom about 20° C. to about 40° C., and in at least one embodiment fromabout 25° C. to about 35° C.; a product temperature of from about 10° C.to about 60° C. including all values and ranges therebetween, in certainembodiments from about 15° C. to about 35° C., and in at least oneembodiment from about 22° C. to about 27° C.; an air flow of from about10 cm/h to about 180 c.m/h including all values and ranges therebetween,in certain embodiments from about 40 c.m/h to about 120 c.m/h, and in atleast one embodiment from about 60 c.m/h to about 80 c.m/h; and anatomizing pressure of from about 0.5 bar to about 4.5 bar including allvalues and ranges therebetween, in certain embodiments from about 1 barto about 3 bar, and in at least one embodiment at about 2 bar. Theresultant controlled release coated microparticles can then bedischarged from the coating chamber and oven cured with the followingparameters: A curing temperature of from about 20° C. to about 65° C.including all values and ranges therebetween, in certain embodimentsfrom about 30° C. to about 55° C., and in at least one embodiment atabout 40° C.; and a curing time of from about 2 hours to about 120 hoursincluding all values and ranges therebetween, in certain embodimentsfrom about 10 hours to about 40 hours, and in at least one embodiment atabout 24 hours. Any other technology resulting in the formulation of themicroparticle controlled release coat consistent with the objects of theinvention can also be used.

Microparticle Dosage Forms

Highly useful dosage forms result when microparticles made fromcompositions containing a bupropion hydrobromide salt, spheronizationaids, and other excipient(s) are coated with controlled releasepolymer(s). The controlled release coated microparticles can then becombined with an excipient mass and/or other pharmaceutical excipients,and compressed into tablets. Conventional tablets can be manufactured bycompressing the coated microparticles with suitable excipients usingknown compression techniques. The dissolution profile of the controlledrelease coated multiparticles is not substantially affected by thecompression of the microparticles into a tablet. The resultant dosageforms enjoy the processing ease associated with the use of excipientmasses and the release properties associated with controlled releasecoated microparticles. Alternatively, the coated microparticles can befilled into capsules.

The forms of administration according to the invention are suitable fororal administration. In certain embodiments the forms of administrationare tablets and capsules. However, the composition of the invention canalso take the form of pellets, beads or microtablets, which can then bepackaged into capsules or compressed into a unitary solid dosage form.Other solid oral dosage forms as disclosed herein can be prepared by theskilled artisan, despite the fact that such other solid oral dosageforms may be more difficult to commercially manufacture.

The present invention also contemplates combinations of differentlycoated microparticles into a dosage form to provide a variety ofdifferent release profiles. For example, in certain embodiments,microparticles with a delayed release profile can be combined with othermicroparticles having a sustained release profile to provide a multiplecomponent controlled release bupropion formulation. In addition, otherembodiments can include one or more further components of immediaterelease bupropion. The immediate release bupropion component can takethe form of uncoated bupropion microparticles or powders; bupropionmicroparticles coated with a highly soluble immediate release coating,such as an OPADRY® type coating, as are known to those skilled in theart, or a combination of any of the foregoing. The multiple componentscan then be blended together in the desired ratio and placed in acapsule, or formed into a tablet. Examples of multiple componentcontrolled release bupropion formulations are described in U.S. Pat. No.6,905,708.

Dose Sipping Technology

The present invention also contemplates an oral delivery system fordelivering microparticles containing bupropion hydrobromide in admixturewith a fluid. For example, an oral delivery system is provided whichcomprises a hollow drug formulation chamber. In at least one embodiment,the chamber has a first end and a second end and contains a formulationin the form of microparticles. The drug formulation comprises bupropionhydrobromide. The system further comprises a fluid passing drugformulation retainer in the first end of the chamber. The retainerprevents release of the microparticles from the first end whilepermitting fluid entry into the chamber. In other embodiments, themicroparticles contained within the chamber comprise bupropionhydrobromide and at least one other drug.

Certain embodiments of the present invention further provide a methodfor orally delivering microparticles containing bupropion hydrobromideformulation in admixture with a fluid. The method involves insertingmicroparticles of bupropion hydrobromide formulation into a hollow drugdelivery chamber of a drug delivery device. The chamber has a first endand a second end. The first end of the chamber has a fluid passing drugformulation retainer. The drug delivery device has a first and secondend. The first end of the drug delivering device is inserted into afluid and the second end is inserted into the mouth of a patient. Thepatient then applies suction to the second end of the device to causedelivery of the fluid and microparticles of bupropion hydrobromideformulation into the patient's mouth.

The term “drug formulation retainer” as used herein, refers to a valve,plug or restriction, or the like that prevents passage of the drugformulation from the device. By “fluid passing drug formulationretainer” is intended a valve, plug or restriction or the like thatallows for passage of fluids but does not allow for passage of otheringredients such as the drug formulation that is contained in thedelivery device.

The dispensing device of this embodiment of the invention finds usewhere it is inconvenient or unsafe to use solid oral dosage forms suchas capsules or tablets. The devices can be particularly useful ingeriatric or pediatric patient populations but they can also be usefulfor those who have difficulty swallowing capsules or tablets. A singledelivery device or several devices can be administered to a patientduring a therapeutic program.

Generally the device is in prepared form prior to placement in a fluid.In at least one embodiment the dispensing device comprises a hollow drugformulation chamber with a first end and a second end. Contained withinthe chamber are drug formulation and fluid passing drug formulationretainers. The fluid passing drug formulation retainer comprises arestriction and a one-way plug. The diameter of the opening is smallerthan the plug. In at least one embodiment the restriction is made bycrimping an end of the chamber. The second end of the chamber has a drugformulation retainer for preventing release of the plug. In at least oneembodiment the retainer is prepared by crimping the end of the chamber.Microparticles of bupropion hydrobromide are then placed in the chamber.An end-cap is placed over the second end of the chamber prior to use toprevent release of the drug formulation. In prepared form, the plugsubstantially seals the first end of the chamber, thereby preventingloss of the drug formulation from the first end.

The device can be formed from any suitable material that is physicallyand/or chemically compatible with both the active drug and the liquiddiluent to be mixed therein. In certain embodiments, representativematerials for forming devices including the drug formulation chamber,the elongated tubular member, the end caps and tabs, include, withoutlimitation, paper, plastic such as propylene/styrene copolymers,polyproylene, high density polyethylene, low density polyethylene andthe like. The devices can have an inner diameter of from about 3 mm toabout 8 mm including all values and ranges therebetween, and a wallthickness of from about 0.1 mm to about 0.4 mm including all values andranges therebetween. The devices can be from about 10 cm to about 30 cmin length including all values and ranges therebetween.

The fluid passing drug formulation retainer permits the free flow ofliquid medium but prohibits passage of the drug formulation from thedevice prior to delivery. Where the retainer comprises a one-way plug orvalve, the plug or valve will seal the straw at atmospheric pressure.When suction is applied, fluid will be drawn around the plug and intothe drug formulation chamber. Further, the plug has a density of lessthan one so that it will ascend to the top as the drug formulation isdelivered into the oral cavity. When suction is no longer applied, theplug will remain in the highest position it reached during sipping. Theplug can be prepared from closed cell polyethylene foam such asETHAFOAM®. Other forms of one way plugs can be a balloon of elastomericmaterial, a one-way mechanical ball valve and the like.

Examples of fluid that can be used for suspending the drug formulationby sipping through the drug formulation chamber include any palatableliquid such as water, juice, milk, soda, coffee, tea etc. Care must betaken to ensure compatibility of the fluid with the drug formulation.

In at least one embodiment, a dose sipping delivery device according tothe present invention can be prepared as follows. Jumbo size straws withan inside diameter of about 0.21 inches and a length of about 8 inchesare heat sealed at one end. The seal is partially cut off so that the“one-way” plug cannot escape. The partially sealed end is enclosed byhalf of a size 1 hard gelatin capsule. Microparticles are then placedinside the open end of the straw. A “one-way” plug made of closed cellpolyethylene foam (e.g. MICROFOAM®) is trimmed to snugly fit inside thestraw. The plug is then placed inside the straw, on top of themicroparticles. During operation, the plug end of the straw is placedinto a glass of water and the protective gelatin capsule on the top ofthe straw is removed. By slowly applying suction through the partiallysealed end of the straw, the microparticles are sucked into the mouthand easily swallowed.

Osmotic Dosage Forms

Osmotic dosage forms, osmotic delivery devices, modified release osmoticdosage forms, or osmosis-controlled extended-release systems are termsused interchangeably herein and are defined to mean dosage forms whichforcibly dispense the bupropion hydrobromide salt by pressure created byosmosis or by osmosis and diffusion of fluid into a material whichexpands and forces the bupropion hydrobromide salt to be dispensed fromthe osmotic dosage form. Osmosis can be defined as the flow of solventfrom a compartment with a low concentration of solute to a compartmentwith a high concentration of solute. The two compartments are separatedby a membrane, wall, or coat, which allows flow of solvent (a liquid,aqueous media, or biological fluids) but not the solute. Non-limitingexamples of such membranes include a semipermeable membrane,microporous, asymmetric membrane, which asymmetric membrane can bepermeable, semipermeable, perforated, or unperforated. Such membrane candeliver the bupropion hydrobromide salt by osmotic pumping, diffusion orthe combined mechanisms of diffusion and osmotic pumping. Thus, inprinciple, osmosis controlled release of the bupropion hydrobromide saltinvolves osmotic transport of an aqueous media into the osmotic dosageform followed by dissolution of the bupropion hydrobromide salt and thesubsequent transport of the saturated solution of the bupropionhydrobromide salt by osmotic pumping of the solution through at leastone passageway in the semipermeable membrane or by a combination ofosmosis and diffusion through the semipermeable membrane.

It is well known to one of ordinary skill in the art that the desiredin-vitro release rate and the in-vivo pharmacokinetic parameters can beinfluenced by several factors, such as for example, the amount of thebupropion hydrobromide salt used to form the core, the amount ofpharmaceutically acceptable excipient used to form the core, the type ofpharmaceutically acceptable excipient used to form the core, the amountor type of any other materials used to form the core such as, forexample, osmagents (the term osmagent, osmotically effective solutes,osmotically effective compound and osmotic agents are usedinterchangeably herein) osmopolymers, and any combination thereof. Therelease profile can also be influenced by the material used to form thesemipermeable membrane covering the core or by the material used to formany coating, such as a controlled release coating. With these factors inmind, an osmotic device can therefore be designed to exhibit an in-vitrorelease rate such that in certain embodiments, after about 2 hours fromabout 0 to about 20% by weight of the bupropion hydrobromide salt isreleased, after about 4 hours from about 15% to about 45% by weight ofthe bupropion hydrobromide salt is released, after about 8 hours, fromabout 40% to about 90% by weight of the bupropion hydrobromide salt isreleased, and after about 16 hours, more than about 80% by weight of thebupropion hydrobromide salt is released, when measured for example byusing a USP Type 1 apparatus (Rotating Basket Method) in 900 ml water,0.1N HCl, 0.1NHCl+0.1% Cetrimide, USP Buffer pH 1.5, Acetate Buffer pH4.5, Phosphate Buffer, pH 6.5 or Phosphate Buffer pH 7.4 at 75 rpm at37° C.±0.5° C. Alternatively dissolution may be effected in USP-3 mediasuch as SGF pH 1.2, Acetate Buffer at pH 4.5 or phosphate buffer at pH6.8.

Osmotic devices also may be designed to achieve an in-vitro release ofno more than about 40% after about 2 hours, from about 40% to about 75%release after about 4 hours, at least about 75% after about 8 hours, andat least about 85% after about 16 hours when assayed using a dissolutionmedium such as identified above or known in the art.

In certain embodiments of the present invention, an osmotic dosage formis provided having a core comprising the bupropion hydrobromide salt andone or more excipients. In at least one embodiment the osmotic dosageform comprises an osmagent. The osmotic delivery system for example, canbe in the form of a tablet or capsule containing microparticles.

In certain embodiments, the core of the osmotic dosage form comprises awater swellable polymer, non-limiting examples of which includehydroxypropyl cellulose, alkylcellulose, hydroxyalkylcellulose,polyalkylene oxide, polyethylene oxide, and mixtures thereof. A bindercan be included in the core of certain embodiments of the osmotic dosageform to increase the core's mechanical strength. Non-limiting examplesof binders include polyvinyl pyrollidine, carboxyvinyl polymer,methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, a low molecular weight polyethylene oxidepolymer, hydroxypropylmethylcellulose, dextrin, maltodextrin, gelatin,polyvinyl alcohol, xanthan gum, carbomers, caragheen, starchderivatives, and mixtures thereof. Lubricants can be included in certainembodiments of the osmotic dosage form to provide decreased frictionbetween the solid and die wall during tablet manufacturing. Non-limitingexamples of lubricants include stearic acid, magnesium stearate,glyceryl behenate, talc, mineral oil, sodium stearyl fumarate,hydrogenated vegetable oil, sodium benzoate, calcium stearate, andmixtures thereof. In other embodiments, additional inert excipientsconsistent with the objects of the invention can also be included in thecore of the osmotic dosage form to facilitate the preparation and/orimprove patient acceptability of the final osmotic dosage form asdescribed herein. Suitable inert excipients are well known to theskilled artisan and can be found in the relevant literature, for examplein the Handbook of Pharmaceutical Excipients (Rowe et. al., 4th Ed.,Pharmaceutical Press, 2003).

In at least one embodiment, a modified release osmotic dosage formcomprises bupropion hydrobromide in a therapeutically effective amount,which releases the bupropion hydrobromide by forcibly dispensing thebupropion hydrobromide from a core via a semipermeable membrane bydiffusion and/or at least one passageway in the membrane by osmoticpumping (i) all or in part by pressure created in the core by osmosisi.e., positive hydrostatic pressure of a liquid, solvent, biologicalfluid or aqueous media and/or all or in part by the expansion of aswellable material which forces the bupropion hydrobromide to bedispensed from the core of the dosage form, and (ii) is formulated suchthat the dosage form exhibits an in-vitro release rate such that afterabout 2 hours from about 0% to about 20% by weight of the bupropionhydrobromide salt is released, after about 4 hours from about 15% toabout 45% by weight of the bupropion hydrobromide salt is released,after about 8 hours, from about 40% to about 90% by weight of thebupropion hydrobromide salt is released, and after about 16 hours, morethan about 80% by weight of the bupropion hydrobromide salt is released.

In at least one embodiment, the modified release dosage form comprisesan osmotic delivery device comprising a homogenous solid core comprisingsubstantially the bupropion hydrobromide salt present in atherapeutically effective amount with at least one pharmaceuticallyacceptable excipient, said core surrounded by a semipermeable membranewhich permits entry of an aqueous liquid into the core and delivery ofthe bupropion hydrobromide salt from the core to the exterior of thedosage form through at least one passageway or by a combination ofosmosis and diffusion such that the dosage form exhibits an in-vitrorelease rate such that after about 2 hours from about 0% to about 20% byweight of the bupropion hydrobromide salt is released, after about 4hours from about 15% to about 45% by weight of the bupropionhydrobromide salt is released, after about 8 hours, from about 40% toabout 90% by weight of the bupropion hydrobromide salt is released, andafter about 16 hours, more than about 80% by weight of the bupropionhydrobromide salt is released. In at least one such embodiment thein-vitro release rate of the bupropion hydrobromide salt is such thatafter about 2 hours no more than about 40% is released, after about 4hours from about 40% to about 75% is released, after about 8 hours atleast about 75% is released, and after about 16 hours at least about 85%is released.

In at least one embodiment, the modified release dosage form comprises amultiparticulate dosage form, each microparticle comprising an osmoticdelivery device, each microparticle comprising a homogenous solid corecomprising substantially the bupropion hydrobromide salt with at leastone pharmaceutically acceptable excipient, said core of eachmicroparticle surrounded by a semipermeable membrane which permits entryof an aqueous liquid into the core and delivery of the bupropionhydrobromide salt from the core to the exterior of the dosage formthrough a plurality of pores formed in the semipermeable membrane byinclusion of a pore forming agent in the membrane or by a combination ofosmosis and diffusion so as to allow communication of the core with theoutside of the device for delivery of the bupropion hydrobromide saltand is formulated such that the dosage form comprises a therapeuticallyeffective amount of the bupropion hydrobromide salt and exhibits anin-vitro release rate such that after about 2 hours from about 0% toabout 20% by weight of the bupropion hydrobromide salt is released,after about 4 hours from about 15% to about 45% by weight of thebupropion hydrobromide salt is released, after about 8 hours, from about40% to about 90% by weight of the bupropion hydrobromide salt isreleased, and after about 16 hours, more than about 80% by weight of thebupropion hydrobromide salt is released. In at least one such embodimentthe in-vitro release rate of the bupropion hydrobromide salt is suchthat after about 2 hours no more than about 40% is released, after about4 hours from about 40% to about 75% is released, after about 8 hours atleast about 75% is released and after about 16 hours at least about 85%is released.

In at least one embodiment, the modified release dosage form comprises amultiparticulate dosage form, each microparticle comprising an osmoticdelivery device, each microparticle comprising a homogenous solid corecomprising substantially the bupropion hydrobromide salt in admixturewith at least one pharmaceutically acceptable excipient, an osmagentand/or an osmopolymer, said core of each microparticle surrounded by asemipermeable membrane which permits entry of an aqueous liquid into thecore and delivery of the bupropion hydrobromide salt from the core tothe exterior of the dosage form through a plurality of pores formed inthe semipermeable membrane by inclusion of a pore forming agent in themembrane or by a combination of osmosis and by diffusion so as to allowcommunication of the core with the outside of the device for delivery ofthe bupropion hydrobromide salt and is formulated such that the dosageform comprises a therapeutically effective amount of the bupropionhydrobromide salt and exhibits an in-vitro release rate such that afterabout 2 hours from about 0% to about 20% by weight of the bupropionhydrobromide salt is released, after about 4 hours from about 15% toabout 45% by weight of the bupropion hydrobromide salt is released,after about 8 hours, from about 40% to about 90% by weight of thebupropion hydrobromide salt is released, and after about 16 hours, morethan about 80% by weight of the bupropion hydrobromide salt is released.In at least one such embodiment the in-vitro release rate of thebupropion hydrobromide salt is such that after about 2 hours no morethan about 40% is released, after about 4 hours from about 40% to about75% is released, after about 8 hours at least about 75% is released andafter about 16 hours at least about 85% is released.

In at least one embodiment, the modified release dosage form comprises amultiparticulate dosage form, each microparticle comprising a homogenoussolid core comprising substantially the bupropion hydrobromide salt withat least one pharmaceutically acceptable excipient in admixture with anosmagent, and/or an osmopolymer, and/or an absorption enhancer, saidmicroparticles compressed into a tablet together with at least onepharmaceutically acceptable excipient, said tablet surrounded by asemipermeable membrane which permits entry of an aqueous liquid into thecore and delivery of the bupropion hydrobromide salt from the tabletinterior to the exterior of the dosage form through at least onepassageway in the semipermeable membrane and/or by diffusion through thesemipermeable membrane so as to allow communication of the tabletinterior with the exterior of the tablet for delivery of the bupropionhydrobromide salt and is formulated such that the dosage form comprisesa therapeutically effective amount of the bupropion hydrobromide saltand exhibits an in-vitro release rate such that after about 2 hours fromabout 0% to about 20% by weight of the bupropion hydrobromide salt isreleased, after about 4 hours from about 15% to about 45% by weight ofthe bupropion hydrobromide salt is released, after about 8 hours, fromabout 40% to about 90% by weight of the bupropion hydrobromide salt isreleased, and after about 16 hours, more than about 80% by weight of thebupropion hydrobromide salt is released. In at least one such embodimentthe in-vitro release profile of the bupropion hydrobromide salt is suchthat after about 2 hours no more than about 40% is released, after about4 hours from about 40% to about 75% is released, after about 8 hours atleast about 75% is released, and after about 16 hours at least about 85%is released.

In at least one embodiment, the modified release dosage form comprises amultiparticulate dosage form, each microparticle comprising a sugarsphere or nonpareil bead coated with at least one layer comprisingsubstantially the bupropion hydrobromide salt with at least onepharmaceutically acceptable excipient, said at least one layersurrounded by a semipermeable membrane which permits entry of an aqueousliquid into the layer and delivery of the bupropion hydrobromide saltfrom the layer to the exterior of the dosage form through a plurality ofpores formed in the semipermeable membrane by inclusion of a poreforming agent in the membrane and/or by diffusion so as to allowcommunication of the core with the outside of the device for delivery ofthe bupropion hydrobromide salt and is formulated such that the dosageform comprises a therapeutically effective amount of the bupropionhydrobromide salt and exhibits an in-vitro release rate such that afterabout 2 hours from about 0% to about 20% by weight of the bupropionhydrobromide salt is released, after about 4 hours from about 15% toabout 45% by weight of the bupropion hydrobromide salt is released,after about 8 hours, from about 40% to about 90% by weight of thebupropion hydrobromide salt is released, and after about 16 hours, morethan about 80% by weight of the bupropion hydrobromide salt is released.In at least one such embodiment the in-vitro release profile of thebupropion hydrobromide salt is such that after about 2 hours no morethan about 40% is released, after about 4 hours from about 40% to about75% is released, after about 8 hours at least about 75% is released andafter about 16 hours at least about 85% is released.

In at least one embodiment, the modified release dosage form comprises amultiparticulate dosage form, each microparticle comprising a sugarsphere or nonpareil bead coated with at least one layer comprisingsubstantially the bupropion hydrobromide salt in admixture with at leastone pharmaceutically acceptable excipient, an osmagent and/or anosmopolymer, said at least one layer surrounded by a semipermeablemembrane which permits entry of an aqueous liquid into the layer anddelivery of the bupropion hydrobromide salt from the layer to theexterior of the dosage form through a plurality of pores formed in thesemipermeable membrane by inclusion of a pore forming agent in themembrane and/or by diffusion so as to allow communication of the corewith the outside of the device for delivery of the bupropionhydrobromide salt and is formulated such that the dosage form comprisesa therapeutically effective amount of the bupropion hydrobromide saltand exhibits an in-vitro release rate such that after about 2 hours fromabout 0% to about 20% by weight of the bupropion hydrobromide salt isreleased, after about 4 hours from about 15% to about 45% by weight ofthe bupropion hydrobromide salt is released, after about 8 hours, fromabout 40% to about 90% by weight of the bupropion hydrobromide salt isreleased, and after about 16 hours, more than about 80% by weight of thebupropion hydrobromide salt is released. In at least one such embodimentthe in-vitro release profile of bupropion hydrobromide salt is such thatafter about 2 hours no more than about 40% is released, after about 4hours from about 40% to about 75% is released, after about 8 hours atleast about 75% is released and after about 16 hours at least about 85%is released.

In at least one embodiment, the modified release dosage form comprises amodified release osmotic dosage form comprising a homogenous corecomprising a therapeutically effective amount of the bupropionhydrobromide salt in admixture with an osmagent, and/or an osmopolymer,and/or and absorption enhancer, said core surrounded by a nontoxic wall,membrane or coat, such as for example a semipermeable membrane whichpermits entry of an aqueous liquid into the core and delivery of thebupropion hydrobromide salt from the core to the exterior of the dosageform through at least one passageway in the semipermeable membraneand/or by diffusion through the membrane so as to allow communication ofthe core with the outside of the dosage form for delivery of thebupropion hydrobromide salt and is formulated such that the dosage formexhibits an in-vitro release rate such that after about 2 hours fromabout 0% to about 20% by weight of the bupropion hydrobromide salt isreleased, after about 4 hours from about 15% to about 45% by weight ofthe bupropion hydrobromide salt is released, after about 8 hours, fromabout 40% to about 90% by weight of the bupropion hydrobromide salt isreleased, and after about 16 hours, more than about 80% by weight of thebupropion hydrobromide salt is released. In at least one such embodimentthe in-vitro release profile of bupropion hydrobromide salt is such thatafter about 2 hours no more than about 40% is released, after about 4hours from about 40% to about 75% is released, after about 8 hours atleast about 75% is released and after about 16 hours at least about 85%is released.

In at least one embodiment the modified release dosage form comprises anosmotic delivery device comprising the bupropion hydrobromide saltpresent in a therapeutically effective amount in a layered, contactingarrangement with a swellable material composition to yield a solid corewith two or more layers, which core is surrounded by a nontoxic wall,membrane or coat, such as for example a semipermeable membrane whichpermits entry of an aqueous liquid into the core and delivery of thebupropion hydrobromide salt from the core to the exterior of the dosageform through at least one passageway in the semipermeable membrane or byosmosis and diffusion through the membrane so as to allow communicationof the core with the outside of the dosage form for delivery of thebupropion hydrobromide salt and is formulated such that the dosage formexhibits an in-vitro release rate such that after about 2 hours fromabout 0% to about 20% by weight of the bupropion hydrobromide salt isreleased, after about 4 hours from about 15% to about 45% by weight ofthe bupropion hydrobromide salt is released, after about 8 hours, fromabout 40% to about 90% by weight of the bupropion hydrobromide salt isreleased, and after about 16 hours, more than about 80% by weight of thebupropion hydrobromide salt is released. In at least one such embodimentthe in-vitro release profile of the bupropion hydrobromide salt is suchthat after about 2 hours no more than about 40% is released, after about4 hours about 40% to about 75% is released, after about 8 hours at leastabout 75% is released and after about 16 hours at least about 85% isreleased.

In at least one embodiment, the modified release dosage form comprisesan osmotic delivery device comprising a core and a membrane surroundingsaid core, said core comprising a therapeutically effective amount ofthe bupropion hydrobromide salt, and optionally at least one means forforcibly dispensing the bupropion hydrobromide salt from the device,said membrane comprising at least one means for the exit of thebupropion hydrobromide salt from the device, said device formulated suchthat when the device is in an aqueous medium, the bupropion hydrobromidesalt, and optionally the at least one means for forcibly dispensing thebupropion hydrobromide salt from the device and the at least one meansfor the exit of the bupropion hydrobromide salt from the devicecooperatively function to exhibit an in-vitro release rate such thatafter about 2 hours from about 0% to about 20% by weight of thebupropion hydrobromide salt is released, after about 4 hours from about15% to about 45% by weight of the bupropion hydrobromide salt isreleased, after about 8 hours, from about 40% to about 90% by weight ofthe bupropion hydrobromide salt is released, and after about 16 hours,more than about 80% by weight of the bupropion hydrobromide salt isreleased. In at least one such embodiment the in-vitro release profileof the bupropion hydrobromide salt is such that after about 2 hours nomore than about 40% is released, after about 4 hours from about 40% toabout 75% is released, after about 8 hours at least about 75% isreleased and after about 16 hours at least about 85% is released.

In at least one embodiment, the modified release dosage form comprisesan osmotic delivery device comprising a core and a membrane surroundingsaid core, said core comprising a therapeutically effective amount ofthe bupropion hydrobromide salt, at least one means for increasing thehydrostatic pressure inside the membrane and optionally at least onemeans for forcibly dispensing the bupropion hydrobromide salt from thedevice, said membrane comprising at least one means for the exit of thebupropion hydrobromide salt from the device, said device formulated suchthat when the device is in an aqueous medium, the at least one means forincreasing the hydrostatic pressure inside the membrane, and optionallythe at least one means for forcibly dispensing the bupropionhydrobromide salt from the device and the at least one means for theexit of the bupropion hydrobromide salt cooperatively function toexhibit an in-vitro release rate such that after about 2 hours fromabout 0% to about 20% by weight of the bupropion hydrobromide salt isreleased, after about 4 hours from about 15% to about 45% by weight ofthe bupropion hydrobromide salt is released, after about 8 hours, fromabout 40% to about 90% by weight of the bupropion hydrobromide salt isreleased, and after about 16 hours, more than about 80% by weight of thebupropion hydrobromide salt is released. In at least one such embodimentthe in-vitro release profile of the bupropion hydrobromide salt is suchthat after about 2 hours no more than about 40% is released, after about4 hours from about 40% to about 75% is released, after about 8 hours atleast about 75% is released and after about 16 hours at least about 85%is released.

Certain embodiments of the invention are directed to once-a-daybupropion hydrobromide sustained release formulations that arebioequivalent according to FDA guidelines to WELLBUTRIN™ ER orZYBANT™/WELLBUTRINT™ SR when administered once-daily to a subject inneed thereof and wherein the bupropion hydrobromide salt contained ismore stable than an equivalent molar amount of the bupropionhydrochloride salt contained in WELLBUTRINT™ ER or ZYBAN™ when exposedto like conditions, for example when stored for 10 days, 13 days, 14days, 20 days, 24 days, 1 month, 2 months, 3 months, 4 months, 5 months,6 months, or more under accelerated storage conditions (e.g. 40 degreesC., 75% relative humidity). In at least one embodiment the inventionencompasses 174 mg, 348 mg and 522 mg bupropion hydrobromideformulations that are bioequivalent to bupropion hydrochlorideformulations.

At least one embodiment is directed to topical formulations containingbupropion hydrobromide that can be administered topically, e.g.,transmucosally or transdermally. Particularly, the at least oneembodiment embraces topically administrable gels and patch type deliverydevices which can comprise another active agent such as nicotine.

At least one embodiment is directed to inhalable pulmonary deliverablecompositions containing bupropion hydrobromide that can be administeredvia pulmonary delivery to a subject in need thereof. These compositionscan be produced according to the aerosol technology as known in the art.

At least one embodiment is directed to injectable compositionscomprising an effective amount of bupropion hydrobromide and apharmaceutically acceptable carrier or excipient.

At least one embodiment is directed to a method of treating a conditioncomprising administering any one of the above described osmotic dosageforms to a patient in need of such administration once-daily.

At least one embodiment is directed to a method for administering abupropion hydrobromide salt to the gastrointestinal tract of a human forthe treatment or management of a condition, wherein the methodcomprises: (a) admitting orally into the human a modified release dosageform comprising a bupropion hydrobromide salt, the modified releasedosage form comprising an osmotic dosage form; and (b) administering thebupropion hydrobromide salt from the osmotic dosage form in atherapeutically responsive dose to produce the treatment or managementof the condition such that the osmotic dosage form exhibits an in-vitrorelease rate such that after about 2 hours from about 0% to about 20% byweight of the bupropion hydrobromide salt is released, after about 4hours from about 15% to about 45% by weight of the bupropionhydrobromide salt is released, after about 8 hours, from about 40% toabout 90% by weight of the bupropion hydrobromide salt is released, andafter about 16 hours, more than about 80% by weight of the bupropionhydrobromide salt is released. In at least one such embodiment thein-vitro release profile of the bupropion hydrobromide salt is such thatafter about 2 hours no more than about 40% is released, after about 4hours from about 40% to about 75% is released, after about 8 hours atleast about 75% is released and after about 16 hours at least about 85%is released.

At least one embodiment is directed to a method for administering abupropion hydrobromide salt to the gastrointestinal tract of a human forthe treatment or management of a condition, wherein the methodcomprises: (a) admitting orally into the human a modified release dosageform comprising a core and a membrane surrounding said core, said corecomprising the bupropion hydrobromide salt and optionally a means forforcibly dispensing the bupropion hydrobromide salt from the device,said membrane comprising at least one means for the exit of thebupropion hydrobromide salt from the dosage form, and (b) administeringthe bupropion hydrobromide salt from the dosage form which is formulatedsuch that when the dosage form is in an aqueous medium, the bupropionhydrobromide salt and optionally the means for forcibly dispensing thebupropion hydrobromide salt and the at least one means for the exit ofthe bupropion hydrobromide salt cooperatively function to exhibit anin-vitro release rate such that after about 2 hours from about 0% toabout 20% by weight of the bupropion hydrobromide salt is released,after about 4 hours from about 15% to about 45% by weight of thebupropion hydrobromide salt is released, after about 8 hours, from about40% to about 90% by weight of the bupropion hydrobromide salt isreleased, and after about 16 hours, more than about 80% by weight of thebupropion hydrobromide salt is released. In at least one such embodimentthe in-vitro release profile of the bupropion hydrobromide salt is suchthat after about 2 hours no more than about 40% is released, after about4 hours from about 40% to about 75% is released, after about 8 hours atleast about 75% is released and after about 16 hours at least about 85%is released.

At least one embodiment is directed to a method for administering abupropion hydrobromide salt to the gastrointestinal tract of a human forthe treatment or management of a condition, wherein the methodcomprises: (a) admitting orally into the human a modified release dosageform comprising a core and a membrane surrounding said core, said corecomprising the bupropion hydrobromide salt, a means for increasing thehydrostatic pressure within the core and optionally a means for forciblydispensing the bupropion hydrobromide salt from the device, saidmembrane comprising at least one means for the exit of the bupropionhydrobromide salt from the dosage form, and (b) administering thebupropion hydrobromide salt from the dosage form which is formulatedsuch that when the dosage form is in an aqueous medium, the bupropionhydrobromide salt, the means for increasing the hydrostatic pressurewithin the core and optionally the means for forcibly dispensing thebupropion hydrobromide salt and the at least one means for the exit ofthe bupropion hydrobromide salt cooperatively function to exhibit anin-vitro release rate such that after about 2 hours from about 0% toabout 20% by weight of the bupropion hydrobromide salt is released,after about 4 hours from about 15% to about 45% by weight of thebupropion hydrobromide salt is released, after about 8 hours, from about40% to about 90% by weight of the bupropion hydrobromide salt isreleased, and after about 16 hours, more than about 80% by weight of thebupropion hydrobromide salt is released. In at least one such embodimentthe in-vitro release profile of the bupropion hydrobromide salt is suchthat after about 2 hours no more than about 40% is released, after about4 hours from about 40% to about 75% is released, after about 8 hours atleast about 75% is released and after about 16 hours at least about 85%is released.

In at least one other embodiment, the osmotic dosage form furthercomprises an immediate release coat for the immediate release of thebupropion hydrobromide salt from the immediate release coat. Inembodiments comprising the immediate release coat, the osmotic dosageform exhibits an in-vitro release rate such that after about 2 hoursfrom about 0% to about 20% by weight of the bupropion hydrobromide saltis released, after about 4 hours from about 15% to about 45% by weightof the bupropion hydrobromide salt is released, after about 8 hours,from about 40% to about 90% by weight of the bupropion hydrobromide saltis released, and after about 16 hours, more than about 80% by weight ofthe bupropion hydrobromide salt is released. In at least one suchembodiment the in-vitro release profile of the bupropion hydrobromidesalt is such that after about 2 hours no more than about 40% isreleased, after about 4 hours from about 40% to about 75% is released,after about 8 hours at least about 75% is released and after about 16hours at least about 85% is released.

In at least one other embodiment, the osmotic dosage forms furthercomprise an inert water-soluble coat covering the semipermeable membraneor coat. This inert water-soluble coat can be impermeable in a firstexternal fluid, while being soluble in a second external fluid. Inembodiments comprising the inert water-soluble coat, the osmotic dosageform exhibits an in-vitro release rate such that after about 2 hoursfrom about 0% to about 20% by weight of the bupropion hydrobromide saltis released, after about 4 hours from about 15% to about 45% by weightof the bupropion hydrobromide salt is released, after about 8 hours,from about 40% to about 90% by weight of the bupropion hydrobromide saltis released, and after about 16 hours, more than about 80% by weight ofthe bupropion hydrobromide salt is released. In at least one suchembodiment the in-vitro release profile of the bupropion hydrobromidesalt is such that after about 2 hours no more than about 40% isreleased, after about 4 hours from about 40% to about 75% is released,after about 8 hours at least about 75% is released and after about 16hours at least about 85% is released.

In at least one other embodiment, the osmotic dosage forms furthercomprise an osmotic subcoat. In certain embodiments comprising theosmotic subcoat, the osmotic dosage form exhibits an in-vitro releaserate such that after about 2 hours from about 0% to about 20% by weightof the bupropion hydrobromide salt is released, after about 4 hours fromabout 15% to about 45% by weight of the bupropion hydrobromide salt isreleased, after about 8 hours, from about 40% to about 90% by weight ofthe bupropion hydrobromide salt is released, and after about 16 hours,more than about 80% by weight of the bupropion hydrobromide salt isreleased. In at least one such embodiment the in-vitro release profileof the bupropion hydrobromide salt is such that after about 2 hours nomore than about 40% is released, after about 4 hours from about 40% toabout 75% is released, after about 8 hours at least about 75% isreleased and after about 16 hours at least about 85% is released.

In at least one other embodiment, the osmotic dosage forms furthercomprise a controlled release coat. The controlled release coat of theosmotic dosage form can, for example, control, extend, and/or delay therelease of the bupropion hydrobromide salt. In certain embodimentscomprising the controlled release coat, the osmotic dosage form exhibitsan in-vitro release rate such that after about 2 hours from about 0% toabout 20% by weight of the bupropion hydrobromide salt is released,after about 4 hours from about 15% to about 45% by weight of thebupropion hydrobromide salt is released, after about 8 hours, from about40% to about 90% by weight of the bupropion hydrobromide salt isreleased, and after about 16 hours, more than about 80% by weight of thebupropion hydrobromide salt is released. In at least one such embodimentthe in-vitro release profile of the bupropion hydrobromide salt is suchthat after about 2 hours no more than about 40% is released, after about4 hours from about 40% to about 75% is released, after about 8 hours atleast about 75% is released and after about 16 hours at least about 85%is released.

In at least one embodiment, the controlled release coat of the osmoticdosage form comprises a material that is soluble or erodible inintestinal juices, substantially pH neutral or basic fluids of fluidshaving a pH higher than gastric fluid, but for the most part insolublein gastric juices or acidic fluids.

In at least one embodiment, the controlled release coat of the osmoticdosage form comprises at least one water-insoluble water-permeablefilm-forming polymer and at least one water-soluble polymer.

In at least one embodiment, the controlled release coat of the osmoticdosage form comprises at least one water-insoluble water-permeablefilm-forming polymer and at least one water-soluble polymer andoptionally at least one plasticizer.

In at least one embodiment, the controlled release coat of the osmoticdosage form comprises at least one water-insoluble water-permeablefilm-forming polymer, at least one water-soluble polymer and at leastone means for the exit of the bupropion hydrobromide salt from the coreof the osmotic dosage form.

In at least one embodiment, the controlled release coat of the osmoticdosage form comprises at least one water-insoluble water-permeablefilm-forming polymer, at least one water-soluble polymer and at leastone passageway.

In at least one embodiment, the controlled release coat of the osmoticdosage form comprises at least one water-insoluble water-permeablefilm-forming polymer, at least one water-soluble polymer and at leastone plasticizer.

In at least one embodiment, the controlled release coat of the osmoticdosage form comprises at least one water-insoluble water-permeablefilm-forming polymer, at least one water-soluble polymer, optionally atleast one plasticizer, and at least one means for the exit of thebupropion hydrobromide salt from the core of the osmotic dosage form.

In at least one embodiment, the controlled release coat of the osmoticdosage form comprises at least one water-insoluble water-permeablefilm-forming polymer, at least one water-soluble polymer, optionally atleast one plasticizer, and at least one passageway.

In at least one embodiment, the controlled release coat of the osmoticdosage form comprises an aqueous dispersion of a neutral ester copolymerwithout any functional groups; a poly glycol having a melting pointgreater than about 55° C., one or more pharmaceutically acceptableexcipients, and optionally at least one means for the exit of thebupropion hydrobromide salt form the core of the osmotic dosage form.This controlled release coat is cured at a temperature at least equal toor greater than the melting point of the polyglycol.

In at least one other embodiment, the controlled release coat of theosmotic dosage form comprises at least one enteric polymer.

In certain embodiments the membrane or wall is permeable to the passageof aqueous media but not to the passage of the bupropion hydrobromidesalt present in the core. The membrane can be, for example, asemipermeable membrane or an asymmetric membrane, which can bepermeable, semipermeable, perforated, or unperforated and can deliverthe bupropion hydrobromide salt by osmotic pumping, or the combinedmechanisms of diffusion and osmotic pumping. The structural integrity ofsuch membranes preferably remain substantially intact during the periodof delivery of the bupropion hydrobromide salt. By “substantiallyintact” it is meant that the semipermeable property of the membrane isnot compromised during the period of delivery of the bupropionhydrobromide salt.

The semipermeable membrane of the osmotic dosage form of certainembodiments comprises at least one pharmaceutically acceptableexcipient, at least one polymer, wax, or combination thereof, althoughappropriately treated inorganic materials such as ceramics, metals orglasses can be used. When the semipermeable membrane comprises at leastone polymer, the molecular weight of the at least one polymer orcombination of polymers are preferably such that the polymer orcombination of polymers is solid at the temperature of use i.e., bothin-vitro and in-vivo.

In certain embodiments, the at least one polymer included in thesemipermeable membrane of the osmotic dosage form can be a celluloseester, such as for example, cellulose acetate, cellulose acetateacetoacetate, cellulose acetate benzoate, cellulose acetatebutylsulfonate, cellulose acetate butyrate, cellulose acetate butyratesulfate, cellulose acetate butyrate valerate. cellulose acetate caprate,cellulose acetate caproate, cellulose acetate caprylate, celluloseacetate carboxymethoxypropionate, cellulose acetate chloroacetate,cellulose acetate dimethaminoacetate, cellulose acetatedimethylaminoacetate, cellulose acetate dimethylsulfamate, celluloseacetate dipalmitate, cellulose acetate dipropylsulfamate, celluloseacetate ethoxyacetate, cellulose acetate ethyl carbamate, celluloseacetate ethyl carbonate, cellulose acetate ethyl oxalate. celluloseacetate furoate, cellulose acetate heptanoate, cellulose acetateheptylate, cellulose acetate isobutyrate, cellulose acetate laurate,cellulose acetate methacrylate, cellulose acetate methoxyacetate,cellulose acetate methylcarbamate, cellulose acetate methylsulfonate,cellulose acetate myristate, cellulose acetate octanoate, celluloseacetate palmitate, cellulose acetate phthalate, cellulose acetatepropionate, cellulose acetate propionate sulfate, cellulose acetatepropionate valerate, cellulose acetate p-toluene sulfonate, celluloseacetate succinate, cellulose acetate sulfate, cellulose acetatetrimellitate, cellulose acetate tripropionate, cellulose acetatevalerate, cellulose benzoate, cellulose butyrate napthylate, cellulosebutyrate, cellulose chlorobenzoate, cellulose cyanoacetates, cellulosedicaprylate, cellulose dioctanoate, cellulose dipentanate, cellulosedipentanlate, cellulose formate, cellulose methacrylates, cellulosemethoxybenzoate, cellulose nitrate, cellulose nitrobenzoate, cellulosephosphate (sodium salt), cellulose phosphinates, cellulose phosphites,cellulose phosphonates, cellulose propionate, cellulose propionatecrotonate, cellulose propionate isobutyrate, cellulose propionatesuccinate, cellulose stearate, cellulose sulfate (sodium salt),cellulose triacetate, cellulose tricaprylate, cellulose triformate,cellulose triheptanoate, cellulose triheptylate, cellulose trilaurate,cellulose trimyristate, cellulose trinitrate, cellulose trioctanoate,cellulose tripalmitate, cellulose tripropionate, cellulose trisuccinate,cellulose trivalerate, cellulose valerate palmitate; a cellulose ether,such as for example, 2-cyanoethyl cellulose, 2-hydroxybutyl methylcellulose, 2-hydroxyethyl cellulose, 2-hydroxyethyl ethyl cellulose,2-hydroxyethyl methyl cellulose, 2-hydroxypropyl cellulose,2-hydroxypropyl methyl cellulose, dimethoxyethyl cellulose acetate,ethyl 2-hydroxylethyl cellulose, ethyl cellulose, ethyl cellulosesulfate, ethylcellulose dimethylsulfamate, methyl cellulose, methylcellulose acetate, methylcyanoethyl cellulose, sodium carboxymethyl2-hydroxyethyl cellulose, sodium carboxymethyl cellulose; a polysulfone,such as for example, polyethersulfones; a polycarbonate; a polyurethane;a polyvinyl acetate; a polyvinyl alcohol; a polyester; a polyalkene suchas polyethylene, ethylene vinyl alcohol copolymer, polypropylene,poly(1,2-dimethyl-1-butenylene), poly(1-bromo-1-butenylene), poly(1,butene), poly(1-chloro-1-butenylene), poly(1-decyl-1-butenylene),poly(1-hexane), poly(1-isopropyl-1-butenylene), poly(1-pentene),poly(3-vinylpyrene), poly(4-methoxyl 1-butenylene),poly(ethylene-co-methyl styrene), poly vinyl-chloride,poly(ethylene-co-tetrafluoroethylene), poly(ethylene-terephthalate),poly(dodecafluorobutoxylethylene), poly(hexafluoroprolylene),poly(hexyloxyethylene), poly(isobutene), poly(isobutene-co-isoprene),poly(isoprene), poly-butadiene, poly[(pentafluoroethypethylene],poly[2-ethylhexyloxy)ethylene], poly(butylethylene),poly(tertbutylethylene), poly(cylclohexylethyl-lene),poly[(cyclohexylmethypethylene], poly(cyclopentylethylene),poly(decylethylene), poly-(dodecy-lethylene), poly(neopentylethylene),poly(propylethylene); a polystyrene, such as for example,poly(2,4-dimethyl styrene), poly(3-methyl styrene),poly(4-methoxystyrene), poly(4-methoxystyrene-stat-styrene),poly(4-methyl styrene), poly(isopentyl styrene), poly(isopropylstyrene), polyvinyl esters or polyvinyl ethers, such as form example,poly(benzoylethylene), poly(butoxyethylene), poly(chloroprene),poly(cyclohexloxyethylene), poly(decyloxyethylene),poly(dichloroethylene), poly(difluoroethylene), poly(vinyl acetate),poly(vinyltrimethyllstyrene); a polysiloxane, such as for example,poly(dimethylsiloxane); a polyacrylic acid derivative, such as forexample, polyacrylates, polymethyl methacrylate, poly(acrylic acid)higher alkyl esters, poly(ethylmethacrylate), poly(hexadecylmethacrylate-co-methylmethacrylate), poly-(methylacrylate-co-styrene),poly(n-butyl methacrylate), poly(n-butyl-acrylate), poly (cyclododecylacrylate), poly(benzyl acrylate), poly(butylacrylate),poly(secbutylacrylate), poly(hexyl acrylate), poly(octyl acrylate),poly(decyl acrylate), poly(dodecyl acrylate), poly(2-methyl butylacrylate), poly(adamantyl methacrylate), poly(benzyl methacrylate),poly(butyl methacrylate), poly(2-ethylhexyl methacrylate), poly(octylmethacrylate), acrylic resins; a polyamide, such as for example,poly(iminoadipoyliminododecamethylene),poly(iminoadipoyliminohexamethylene), polyethers, such as for example,poly(octyloxyethylene), poly(oxyphenylethylene), poly(oxypropylene),poly(pentyloxyethylene), poly(phenoxy styrene),poly(secbutroxylethylene), poly(tert-butoxyethylene); and combinationsthereof.

In at least one embodiment, the at least one wax included in thesemipermeable membrane of the osmotic dosage form can be, for example,insect and animal waxes, such as for example, chinese insect wax,beeswax, spermaceti, fats and wool wax; vegetable waxes, such as forexample, bamboo leaf wax, candelilla wax, carnauba wax, Japan wax,ouricury wax, Jojoba wax, bayberry wax, Douglas-Fir wax, cotton wax,cranberry wax, cape berry wax, rice-bran wax, castor wax, indian cornwax, hydrogenated vegetable oils (e.g., castor, palm, cottonseed,soybean), sorghum grain wax, Spanish moss wax, sugarcane wax, carandawax, bleached wax, Esparto wax, flax wax, Madagascar wax, orange peelwax, shellac wax, sisal hemp wax and rice wax; mineral waxes, such asfor example, Montan wax, peat waxes, petroleum wax, petroleum ceresin,ozokerite wax, microcrystalline wax and paraffins; synthetic waxes, suchas for example, polyethylene wax, Fischer-Tropsch wax, chemicallymodified hydrocarbon waxes, cetyl esters wax; and combinations thereof.

In at least one embodiment, the semipermeable membrane of the osmoticdosage form can comprise a combination of at least one polymer, wax, orcombinations thereof and optionally at least one excipient.

In embodiments where the bupropion hydrobromide salt is released throughthe membrane or wall in a controlled manner by the combined mechanismsof diffusion and osmotic pumping, the membrane or wall can comprise atleast one of the above described polymers and/or waxes or a combinationof polymers, such as for example, cellulose esters, copolymers ofmethacrylate salts and optionally a plasticizer.

The poly(methacrylate) copolymer salts used in the manufacturing of themembrane for the osmotic dosage form can be, for example, insoluble inwater and in digestive fluids, but are permeable to different degrees.Examples of such copolymers are poly(ammonium methacrylate) copolymer RL(EUDRAGIT®RL), poly(ammonium methacrylate) copolymer (type A-USP/NF),poly(aminoalkyl methacrylate) copolymer RL-JSP I), and (ethylacrylate)-(methyl methacrylate)-[(trimethylammonium)-ethylmethacrylate](1:2:0.2) copolymer, MW 150,000. Other examples of such copolymersinclude EUDRAGIT®RS 100: solid polymer, EUDRAGIT®RL 12.5:12.5% solutionin solvent, EUDRAGIT®RL 30 D: 30% aqueous dispersion, and otherequivalent products. The following poly (ammonium methacrylate)copolymers can also be used: ammonium methacrylate copolymer RS(EUDRAGIT®RS), poly(ammonium methacrylate) copolymer (type B-USP/NF),poly(aminoalkyl methacrylate) copolymer (RSL-JSP I), (ethylacrylate)-(Methyl methacrylate)-[(trimethylammonium)-ethyl methacrylate](1:2:0.1) copolymer, PM 150,000. Specific polymers include: EUDRAGIT®RS100: solid polymer, EUDRAGIT®RS 12.5: 12.5% solution in solvent,EUDRAGIT®RS 30 D: 30% aqueous dispersion and other equivalent products.RL is readily water permeable while EUDRAGIT®RS is hardly waterpermeable. By employing mixtures of both EUDRAGIT®RL and EUDRAGIT®RS,membranes having the desired degree of permeability to achieve thein-vitro dissolution rates and in-vivo pharmacokinetic parameters can beprepared.

The use of plasticizers is optional but can be included in the osmoticdosage forms of certain embodiments to modify the properties andcharacteristics of the polymers used in the coats or core of the osmoticdosage forms for convenient processing during manufacture of the coatsand/or the core of the osmotic dosage forms if necessary. As usedherein, the term “plasticizer” includes any compounds capable ofplasticizing or softening a polymer or binder used in invention. Oncethe coat or membrane has been manufactured, certain plasticizers canfunction to increase the hydrophilicity of the coat(s) and/or the coreof the osmotic dosage form in the environment of use. During manufactureof the coat, the plasticizer lowers the melting temperature or glasstransition temperature (softening point temperature) of the polymer orbinder. Plasticizers, such as low molecular weight PEG, can be includedwith a polymer and lower its glass transition temperature or softeningpoint. Plasticizers also can reduce the viscosity of a polymer. Theplasticizer can impart some particularly advantageous physicalproperties to the osmotic device of the invention.

Plasticizers useful in the osmotic dosage form of certain embodiments ofthe invention can include, for example, low molecular weight polymers,oligomers, copolymers, oils, small organic molecules, low molecularweight polyols having aliphatic hydroxyls, ester-type plasticizers,glycol ethers, poly(propylene glycol), multi-block polymers, singleblock polymers, low molecular weight poly(ethylene glycol), citrateester-type plasticizers, triacetin, propylene glycol, glycerin, ethyleneglycol, 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol,diethylene glycol, triethylene glycol, tetraethylene glycol and otherpoly(ethylene glycol) compounds, monopropylene glycol monoisopropylether, propylene glycol monoethyl ether, ethylene glycol monoethylether, diethylene glycol monoethyl ether, sorbitol lactate, ethyllactate, butyl lactate, ethyl glycolate, dibutylsebacate,acetyltributylcitrate, triethyl citrate, acetyl triethyl citrate,tributyl citrate, allyl glycolate and mixtures thereof. It is alsocontemplated and within the scope of the invention, that a combinationof plasticizers can be used in the present formulation. The PEG basedplasticizers are available commercially or can be made by a variety ofmethods, such as disclosed in Poly(ethylene glycol) Chemistry:Biotechnical and Biomedical Applications (J. M. Harris, Ed.; PlenumPress, NY). Once the osmotic dosage form is manufactured, certainplasticizers can function to increase the hydrophilicity of the coat(s)and/or the core of the osmotic dosage form in the environment of use mayit be in-vitro or in-vivo. Accordingly, certain plasticizers canfunction as flux enhancers.

The ratio of cellulose esters:copolymers of methacrylatesalts:plasticizer of the osmotic dosage forms can be, for example, about1% to about 99% of the cellulose ester by weight: about 0.5% to about84% of the copolymers of methacrylate salt by weight: about 0.5% toabout 15% of the plasticizer by weight including all values and rangestherebetween. The total weight percent of all components comprising thewall is 100%.

Aside from the semipermeable membranes of the osmotic dosage formdescribed above, asymmetric membranes can also be used to surround thecore of an osmotic dosage form for the controlled release of thebupropion hydrobromide salt to provide the in-vitro release ratesdescribed above and the therapeutically beneficial in-vivopharmacokinetic parameters for the treatment or management of acondition. Such asymmetric membranes can be permeable, semipermeable,perforated, or unperforated and can deliver the bupropion hydrobromidesalt by osmotic pumping, diffusion or the combined mechanisms ofdiffusion and osmotic pumping. The manufacture and use thereof ofasymmetric membranes for the controlled-release of an active drugthrough one or more asymmetric membranes by osmosis or by a combinationof diffusion osmotic pumping is known.

In certain embodiments of the osmotic dosage form, the semipermeablemembrane can further comprise a flux enhancing, or channeling agent.“Flux enhancing agents” or “channeling agents” are any materials whichfunction to increase the volume of fluid imbibed into the core to enablethe osmotic dosage form to dispense substantially all of the bupropionhydrobromide salt through at least one passageway in the semipermeablemembrane by osmosis or by osmosis and by diffusion through thesemipermeable membrane. The flux enhancing agent dissolves to form pathsin the semipermeable membrane for the fluid to enter the core anddissolve the bupropion hydrobromide salt in the core together with theosmagent, if one is present, but does not allow exit of the bupropionhydrobromide salt. The flux enhancing agent can be any water solublematerial or an enteric material which allows an increase in the volumeof liquid imbibed into the core but does not allow for the exit of thebupropion hydrobromide salt. Such materials can be, for example, sodiumchloride, potassium chloride, sucrose, sorbitol, mannitol, polyethyleneglycol, propylene glycol, hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxypropyl methylcellulose phthalate, celluloseacetate phthalate, polyvinyl alcohols, methacrylic copolymers, andcombinations thereof. Some plasticizers can also function as fluxenhancers by increasing the hydrophilicity of the semipermeable membraneand/or the core of the osmotic dosage form. Flux enhancers or channelingagents can also function as a means for the exit of the bupropionhydrobromide salt from the core if the flux enhancing or channelingagent is used in a sufficient amount.

The expression “passageway” as used herein comprises means and methodssuitable for the metered release of the bupropion hydrobromide salt fromthe core of the osmotic dosage form. The means for the exit of thebupropion hydrobromide salt comprises at least one passageway, includingorifice, bore, aperture, pore, porous element, hollow fiber, capillarytube, porous overlay, or porous element that provides for the osmoticcontrolled release of the bupropion hydrobromide salt. The means for theexit can be linear or tortuous. The means for the exit includes aweakened area of the semipermeable membrane or a material that erodes oris leached from the wall in a fluid environment of use to produce atleast one dimensioned passageway. The means for the exit of thebupropion hydrobromide salt can comprise any leachable material, whichwhen leaches out of the semipermeable membrane forms a passagewaysuitable for the exit of the bupropion hydrobromide salt from the coreof the osmotic dosage form. Such leachable materials can comprise, forexample, a leachable poly(glycolic) acid or poly(lactic) acid polymer inthe semipermeable membrane, a gelatinous filament, poly(vinyl alcohol),leachable polysaccharides, salts, oxides, sorbitol, sucrose or mixturesthereof. The means for exit can also comprise a flux enhancer orchanneling agent if present in a sufficient amount. The means for theexit possesses controlled-release dimensions, such as round, triangular,square and elliptical, for the metered release of the bupropionhydrobromide salt from the dosage form. The dimensions of the means ofthe exit for the bupropion hydrobromide salt is sized such so as toallow the bupropion hydrobromide salt to pass through the means for theexit. The dosage form can be constructed with one or more means for theexit in spaced apart relationship on a single surface or on more thanone surface of the wall.

The expression “fluid environment” denotes an aqueous or biologicalfluid as in a human patient, including the gastrointestinal tract. Themeans for the exit can be preformed for example by mechanical meansafter the semipermeable membrane is applied to the core of the osmoticdosage form, such as for example by mechanical perforation, laserperforation, or by using a properly sized projection on the interior ofa tablet punch to form the means for the exit of the bupropionhydrobromide salt, such as for example a cylindrical or frustoconicalpin which is integral with the inside surface of the upper punch of apunch used to form the osmotic dosage form. Alternatively, the means forthe exit of the bupropion hydrobromide salt can be formed byincorporating a leachable material or pore forming agent into thesemipermeable composition before the semipermeable membrane is appliedto the core of the osmotic dosage form. The means for the exit of thebupropion hydrobromide salt can comprise a combination of the differentexit means described above. The osmotic dosage form can comprise morethan one means for the exit of the bupropion hydrobromide salt includingtwo, three, four, five, six seven, eight, nine ten or more exit meansand can be formed in any place of the osmotic dosage form. The variouspositions of the means for the exit are disclosed. The type, number, anddimension(s) of the means for the exit of the bupropion hydrobromidesalt is such that the dosage form exhibits the desired in-vitro releaserates described herein and can be determined by routine experimentationby those skilled in the pharmaceutical delivery arts. The means for theexit and equipment for forming the means for the exit are known.

The osmotic device can further comprise a controlled release coatsurrounding the semipermeable membrane comprising an enteric or delayedrelease coat that is soluble or erodible in intestinal juices,substantially pH neutral or basic fluids of fluids having a pH higherthan gastric fluid, but for the most part insoluble in gastric juices oracidic fluids. A wide variety of other polymeric materials are known topossess these various solubility properties. Such other polymericmaterials include, for example, cellulose acetate phthalate (CAP),cellulose acetate trimelletate (CAT), poly(vinyl acetate) phthalate(PVAP), hydroxypropyl methyl cellulose phthalate (HP), poly(methacrylateethylacrylate) (1:1) copolymer (MA-EA), poly(methacrylatemethylmethacrylate) (1:1) copolymer (MA-MMA), poly(methacrylatemethylmethacrylate) (1:2) copolymer, EUDRAGIT® L-30-D (MA-EA, 1:1),EUDRAGIT® L-100-55 (MA-EA, 1:1), hyciroxypropyl methylcellulose acetatesuccinate (HPMCAS), COATERIC® (PVAP), AQUATERIC® (CAP), AQUACOAT®(HPMCAS) and combinations thereof. The enteric coat can also comprisedissolution aids, stability modifiers, and bioabsorption enhancers.

In at least one embodiment the controlled release coat of certainosmotic dosage forms include materials such as hydroxypropylcellulose,microcrystalline cellulose (e.g. MCC, AVICEL™), poly (ethylene-vinylacetate) (60:40) copolymer (EVAC), 2-hydroxyethylmethacrylate (HEMA),MMA, terpolymers of HEMA: MMA:MA synthesized in the presence ofN,N′-bis(methacryloyloxyethyloxycarbonylamino)-azobenzene, azopolymers,enteric coated timed release system (TIME CLOCK®), calcium pectinate,and mixtures thereof.

Polymers that can be used in the controlled release coat of osmoticdosage forms of certain embodiments can be, for example, entericmaterials that resist the action of gastric fluid avoiding permeationthrough the semipermeable wall while one or more of the materials in thecore of the dosage form are solubilized in the intestinal tract therebyallowing delivery of the bupropion hydrobromide salt in the core byosmotic pumping in the osmotic dosage form to begin. A material thatadapts to this kind of requirement can be, for example, apoly(vinylpyrrolidone)-vinyl acetate copolymer (e.g. KOLLIDON® VA64),mixed with magnesium stearate and other similar excipients. The coat canalso comprise povidone (e.g. KOLLIDON® K 30), and hydroxypropylmethylcellulose (e.g. METHOCEL® E-15). The materials can be prepared insolutions having different concentrations of polymer according to thedesired solution viscosity. For example, a 10% P/V aqueous solution ofKOLLIDON® K 30 has a viscosity of about 5.5 to about 8.5 cps at 20° C.,and a 2% P/V aqueous solution of METHOCEL® E-15 has a viscosity of about13 to about 18 cps at 20° C.

The controlled release coat of osmotic dosage forms of certainembodiments can comprise one or more materials that do not dissolve,disintegrate, or change their structural integrity in the stomach andduring the period of time that the tablet resides in the stomach, suchas for example a member chosen from the group (a) keratin, keratinsaridarac-tolu, salol (phenyl salicylate), salol beta-naphthylbenzoateand acetotannin, salol with balsam of Peru, salol with tolu, salol withgum mastic, salol and stearic acid, and salol and shellac; (b) a memberchosen from the group of formalized protein, formalized gelatin, andformalized cross-linked gelatin and exchange resins; (c) a member chosenfrom the group of myristic acid-hydrogenated castor oil-cholesterol,stearic acid-mutton tallow, stearic acid-balsam of tolu, and stearicacid-castor oil; (d) a member chosen from the group of shellac,ammoniated shellac, ammoniated shellac-salol, shellac-wool fat,shellac-acetyl alcohol, shellac-stearic acid-balsam of tolu, and shellacn-butyl stearate; (e) a member chosen from the group of abietic acid,methyl abictate, benzoin, balsam of tolu, sandarac, mastic with tolu,and mastic with tolu, and mastic with acetyl alcohol; (f) acrylic resinsrepresented by anionic polymers synthesized from methacrylate acid andmethacrylic acid methyl ester, copolymeric acrylic resins of methacrylicand methacrylic acid and methacrylic acid alkyl esters, copolymers ofalkacrylic acid and alkacrylic acid alkyl esters, acrylic resins such asdimethylaminoethylmethacrylate-butylmethacrylate-methylmethacrylatecopolymer of about 150,000 molecular weight, methacrylicacid-methylmethacrylate 50:50 copolymer of about 135,000 molecularweight, methacrylic acid-methylmethacrylate-30:70-copolymer of about135,000 mol. wt., methacrylicacid-dimethylaminoethyl-methacrylate-ethylacrylate of about 750,000 mol.wt., methacrylic acid-methylmethacrylate-ethylacrylate of about1,000,000 mol. wt., and ethylacrylate-methylmethacrylate-ethylacrylateof about 550,000 mol. wt; and, (g) an enteric composition chosen fromthe group of cellulose acetyl phthalate, cellulose diacetyl phthalate,cellulose triacetyl phthalate, cellulose acetate phthalate,hydroxypropyl methylcellulose phthalate, sodium cellulose acetatephthalate, cellulose ester phthalate, cellulose ether phthalate,methylcellulose phthalate, cellulose ester-ether phthalate,hydroxypropyl cellulose phthalate, alkali salts of cellulose acetatephthalate, alkaline earth salts of cellulose acetate phthalate, calciumsalt of cellulose acetate phthalate, ammonium salt of hydroxypropylmethylcellulose phthalate, cellulose acetate hexahydrophthalate,hydroxypropyl methylcellulose hexahydrophthalate, polyvinyl acetatephthalate diethyl phthalate, dibutyl phthalate, dialkyl phthalatewherein the alkyl comprises from about 1 to about 7 straight andbranched alkyl groups, aryl phthalates, and other materials known to oneor ordinary skill in the art. Combinations thereof are operable.

Accordingly, in at least one other embodiment, the controlled releasecoat of osmotic dosage forms of certain embodiments comprises awater-insoluble water-permeable film-forming polymer, water-solublepolymer, and optionally a plasticizer and/or a pore-forming agent. Thewater-insoluble, water-permeable film-forming polymers useful for themanufacture of the controlled release coat can be cellulose ethers, suchas for example, ethyl celluloses chosen from the group of ethylcellulose grade PR100, ethyl cellulose grade PR20, cellulose esters,polyvinyl alcohol, and any combination thereof. The water-solublepolymers useful for the controlled release coat can be, for example,polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropylcellulose, and any combination thereof.

The skilled artisan will appreciate that that the desired in-vitrorelease rates described herein for the bupropion hydrobromide salt canbe achieved by controlling the permeability and/or the amount of coatingapplied to the core of the osmotic dosage form. The permeability of thecontrolled release coat, can be altered by varying the ratio of thewater-insoluble, water-permeable film-forming polymer:water-solublepolymer:optionally the plasticizer and/or the quantity of coatingapplied to the core of the osmotic dosage form. A more extended releaseis generally obtained with a higher amount of water-insoluble,water-permeable film forming polymer. The addition of other excipientsto the core of the osmotic dosage form can also alter the permeabilityof the controlled release coat. For example, if the core of the osmoticdosage form comprises a swellable polymer, the amount of plasticizer inthe controlled release coat can be increased to make the coat morepliable as the pressure exerted on a less pliable coat by the swellablepolymer could rupture the coat. Further, the proportion of thewater-insoluble water-permeable film forming polymer and water-solublepolymer can also be altered depending on whether a faster or slowerin-vitro dissolution is desired.

In at least one other embodiment, the controlled release coat of theosmotic dosage form comprises an aqueous dispersion of a neutral estercopolymer without any functional groups; a poly glycol having a meltingpoint greater than about 55° C., and one or more pharmaceuticallyacceptable excipients and cured at a temperature at least equal to orgreater than the melting point of the poly glycol. The manufacture anduse of such coating formulations are known. In brief, examples ofneutral ester copolymers without any functional groups comprising thecoat can be EUDRAGIT® NE30D, EUDRAGIT® NE40D, or mixtures thereof. Thiscoat can comprise hydrophilic agents to promote wetting of the coat whenin contact with gastrointestinal fluids. Such hydrophilic agentsinclude, for example, hydrophilic water-soluble polymers such ashydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC) andcombinations thereof. The poly glycol can be, for example, chosen fromthe group of polyethylene glycol 6000, polyethylene glycol 8000,polyethylene glycol 10000, polyethylene glycol 20000, Poloxamer 188,Poloxamer 338, Poloxamer 407, Polyethylene Oxides, Polyoxyethylene AlkylEthers, and Polyoxyethylene Stearates, and combinations thereof. Thiscontrolled release coat of the osmotic dosage form can further comprisea pore-forming agent. In at least one embodiment the pore former issufficiently insoluble in the aqueous dispersion, and is sufficientlysoluble in the environment of use. Methods for producing such coats areknown.

The controlled release coat of certain embodiments of the osmotic dosageform of certain embodiments of the present invention includes at leastone polymer in an amount sufficient to achieve a controlled release ofthe bupropion hydrobromide salt. Examples of polymers that can be usedin the controlled release coat of these embodiments include celluloseacetate phthalate, cellulose acetate trimaletate, hydroxy propylmethylcellulose phthalate, polyvinyl acetate phthalate, ammoniomethacrylate copolymers such as EUDRAGIT® RS and RL, poly acrylic acidand poly acrylate and methacrylate copolymers such as EUDRAGIT® S and L,polyvinyl acetaldiethylamino acetate, hydroxypropyl methylcelluloseacetate succinate, shellac; hydrogels and gel-forming materials, such ascarboxyvinyl polymers, sodium alginate, sodium carmellose, calciumcarmellose, sodium carboxymethyl starch, poly vinyl alcohol,hydroxyethyl cellulose, methyl cellulose, gelatin, starch, and cellulosebased cross-linked polymers in which the degree of crosslinking is lowso as to facilitate adsorption of water and expansion of the polymermatrix, hydroxypropyl cellulose, hydroxypropyl methylcellulose,polyvinylpyrrolidone, crosslinked starch, microcrystalline cellulose,chitin, aminoacryl-methacrylate copolymer (e.g. EUDRAGIT® RS-PM),pullulan, collagen, casein, agar, gum arabic, sodium carboxymethylcellulose, (swellable hydrophilic polymers) poly(hydroxyalkylmethacrylate) (molecular weight from about 5K to about 5000K),polyvinylpyrrolidone (molecular weight from about 10K to about 360K),anionic and cationic hydrogels, polyvinyl alcohol having a low acetateresidual, a swellable mixture of agar and carboxymethyl cellulose,copolymers of maleic anhydride and styrene, ethylene, propylene orisobutylene, pectin (molecular weight from about 30K to about 300K),polysaccharides such as agar, acacia, karaya, tragacanth, algins andguar, polyacrylamides, POLYOX® polyethylene oxides (molecular weightfrom about 100K to about 5000K), AQUAKEEP® acrylate polymers, diestersof polyglucan, crosslinked polyvinyl alcohol and polyN-vinyl-2-pyrrolidone, sodium starch glycolate (e.g. EXPLOTAB®);hydrophilic polymers such as polysaccharides, methyl cellulose, sodiumor calcium carboxymethyl cellulose, hydroxypropyl methyl cellulose,hydroxypropyl cellulose, hydroxyethyl cellulose, nitro cellulose,carboxymethyl cellulose, cellulose ethers, polyethylene oxides (e.g.POLYOX), methyl ethyl cellulose, ethylhydroxy ethylcellulose, celluloseacetate, cellulose butyrate, cellulose propionate, gelatin, collagen,starch, maltodextrin, pullulan, polyvinyl pyrrolidone, polyvinylalcohol, polyvinyl acetate, glycerol fatty acid esters, polyacrylamide,polyacrylic acid, copolymers of methacrylic acid or methacrylic acid(e.g. EUDRAGIT®), other acrylic acid derivatives, sorbitan esters,natural gums, lecithins, pectin, alginates, ammonia alginate, sodium,calcium, potassium alginates, propylene glycol alginate, agar, and gumssuch as arabic, karaya, locust bean, tragacanth, carrageens, guar,xanthan, scleroglucan and mixtures and blends thereof. In at least oneembodiment of the osmotic dosage form of the present invention, thepolymer is an acrylate dispersion such as EUDRAGIT® NE30D, EUDRAGIT®NE40D, KOLLICOAT® SR 30D, SURELEASE®, or a mixture thereof. The polymercan be present in an amount of from about 20% to about 90% by weight ofthe controlled release coat including all values and rangestherebetween, depending on the controlled release profile desired. Forexample, in certain embodiments of the osmotic dosage form, the polymeris present in an amount of from about 50% to about 95%, in otherembodiments from about 60% to about 90%, and in still other embodimentsabout 75% of the controlled release coat weight.

The controlled release coat of certain embodiments of the osmotic dosageform of the present invention can also include one or morepharmaceutically acceptable excipients such as lubricants, emulsifiers,anti-foaming agents, plasticisers, solvents and the like.

Lubricants can be included in the controlled release coat of certainembodiments of the osmotic dosage form of the present invention to helpreduce friction of coated microparticles during manufacturing. Thelubricants that can be used in the controlled release coat include butare not limited to adipic acid, magnesium stearate, calcium stearate,zinc stearate, calcium silicate, magnesium silicate, hydrogenatedvegetable oils, sodium chloride, sterotex, polyoxyethylene, glycerylmonostearate, talc, polyethylene glycol, sodium benzoate, sodium laurylsulfate, magnesium lauryl sulfate, sodium stearyl fumarate, lightmineral oil, waxy fatty acid esters such as glyceryl behenate, (i.e.COMPRITOL™), STEAR-O-WETT™ and MYVATEX™ TL. Combinations of theselubricants are operable. In at least one embodiment, the lubricant isselected from magnesium stearate, talc and a mixture thereof. Thelubricant(s) can each be present in an amount of from about 0.1% toabout 80% of the controlled release coat weight including all values andranges therebetween. For example, in certain embodiments the lubricantis present in an amount of from about 0.5% to about 20%, in otherembodiments from about 0.8% to about 10%, and in still other embodimentsabout 1.5% of the controlled release coat weight.

Emulsifying agent(s) (also called emulsifiers or emulgents) can beincluded in the controlled release coat of the osmotic dosage forms ofcertain embodiments of the present invention to facilitate actualemulsification during manufacture of the coat, and also to increase orensure emulsion stability during the shelf-life of the product.Emulsifying agents useful for the controlled release coat composition ofthe osmotic dosage form include, but are not limited to naturallyoccurring materials and their semi synthetic derivatives, such as thepolysaccharides, as well as glycerol esters, cellulose ethers, sorbitanesters (e.g. sorbitan monooleate or SPAN™ 80), and polysorbates (e.g.TWEEN™ 80). Combinations of emulsifying agents are operable. Theemulsifying agent(s) can be present in an amount of from about 0.01% toabout 0.25% of the controlled release coat weight including all valuesand ranges therebetween. For example, in certain embodiments theemulsifying agent is present in an amount of from about 0.01% to about0.15%, in other embodiments from about 0.01% to about 0.07%, and instill other embodiments about 0.03% of the controlled release coatweight.

Anti-foaming agent(s) can be included in the controlled release coat ofthe osmotic dosage form of certain embodiments of the present inventionto reduce frothing or foaming during manufacture of the coat.Anti-foaming agents useful for the controlled release coat compositionof the osmotic dosage form include, but are not limited to simethicone,polyglycol, silicon oil and mixtures thereof. In at least one embodimentthe anti-foaming agent is Simethicone C. The anti-foaming agent can bepresent in an amount of from about 0.01% to about 10% of the controlledrelease coat weight including all values and ranges therebetween. Forexample, in certain embodiments the anti-foaming agent is present in anamount of from about 0.05% to about 1%, in other embodiments from about0.1% to about 0.3%, and in still other embodiments about 0.15% of thecontrolled release coat weight.

It is contemplated that in certain embodiments, other excipientsconsistent with the objects of the present invention can also be used inthe controlled release coat of the osmotic dosage form.

In at least one embodiment, the controlled release coat of the osmoticdosage form includes about 75% EUDRAGIT® NE30D, about 1.5% Magnesiumstearate, about 1.5% Talc, about 0.03% TWEEN™ 80, about 0.15%Simethicone C, and about 21.82% water, by weight of the controlledrelease coat composition.

The osmotic dosage form of certain embodiments can be made according toany one of the methods described herein. In a prophetic example ofcertain embodiments of osmotic dosage forms of the present invention,the manufacturing process for the controlled release coat of the osmoticdosage form can hypothetically be as follows: Water is split into twoportions of about 15% and about 85%. The anti-foaming agent and theemulsifying agent are then added to the 15% water portion, and mixed atabout 300 rpm to form portion A. In at least one embodiment, theanti-foaming agent is Simethicone C, and the emulsifying agent is TWEEN™80. A first lubricant is then added to the 85% water portion and mixedat about 9500 rpm to form portion B. In at least one embodiment, thefirst lubricant is talc. Then portion A is mixed with portion B, asecond lubricant is slowly added, and mixed at about 700 rpm overnight.In at least one embodiment, the second lubricant is magnesium stearate.Finally, an aqueous dispersion of a neutral ester copolymer is added andmixed for about 30 minutes at about 500 rpm. In at least one embodiment,the aqueous dispersion of a neutral ester copolymer is EUDRAGIT® NE30D.The resultant coat solution can then be used to coat the osmoticsubcoated microparticles to about a 35% weight gain with the followingparameters: An inlet temperature of from about 10° C. to about 60° C.including all values and ranges therebetween, in certain embodimentsfrom about 20° C. to about 40° C., and in at least one embodiment fromabout 25° C. to about 35° C.; an outlet temperature of from about 10° C.to about 60° C. including all values and ranges therebetween, in certainembodiments from about 20° C. to about 40° C., and in at least oneembodiment from about 25° C. to about 35° C.; a product temperature offrom about 10° C. to about 60° C. including all values and rangestherebetween, in certain embodiments from about 15° C. to about 35° C.,and in at least one embodiment from about 22° C. to about 27° C.; an airflow of from about 10 cm/h to about 180 cm/h including all values andranges therebetween, in certain embodiments from about 40 cm/h to about120 cm/h, and in at least one embodiment from about 60 cm/h to about 80cm/h; and an atomizing pressure of from about 0.5 bar to about 4.5 barincluding all values and ranges therebetween, in certain embodimentsfrom about 1 bar to about 3 bar, and in at least one embodiment at about2 bar. The resultant coated microparticles can then be discharged fromthe coating chamber and overcured with the following parameters: Acuring temperature of from about 20° C. to about 65° C. including allvalues and ranges therebetween, in certain embodiments from about 30° C.to about 55° C., and in at least one embodiment at about 40° C.; and acuring time of from about 2 hours to about 120 hours including allvalues and ranges therebetween, in certain embodiments from about 10hours to about 40 hours, and in at least one embodiment at about 24hours. Any other technology resulting in the coating formulation of thecontrolled release coat of the osmotic dosage form that is consistentwith the objects of the invention can also be used.

In at least one other embodiment, the osmotic dosage forms comprise awater-soluble or rapidly dissolving coat between the semipermeablemembrane and the controlled release coat. The rapidly dissolving coatcan be soluble in the buccal cavity and/or upper GI tract, such as thestomach, duodenum, jejunum or upper small intestines. Materials suitablefor the manufacture of the water-soluble coat are known. In certainembodiments, the rapidly dissolving coat can be soluble in saliva,gastric juices, or acidic fluids. Materials which are suitable formaking the water soluble coat or layer can comprise, for example, watersoluble polysaccharide gums such as carrageenan, fucoidan, gum ghatti,tragacanth, arabinogalactan, pectin, and xanthan; water-soluble salts ofpolysaccharide gums such as sodium alginate, sodium tragacanthin, andsodium gum ghattate; water-soluble hydroxyalkylcellulose wherein thealkyl member is straight or branched of 1 to 7 carbons such as, forexample, hydroxymethylcellulose, hydroxyethylcellulose, andhydroxypropylcellulose; synthetic water-soluble cellulose-based laminaformers such as, for example, methyl cellulose and its hydroxyalkylmethylcellulose cellulose derivatives such as a member chosen from thegroup of hydroxyethyl methylcellulose, hydroxypropyl methylcellulose,and hydroxybutyl methylcellulose; croscarmellose sodium; other cellulosepolymers such as sodium carboxymethylcellulose; and mixtures thereof.Other lamina forming materials that can be used for this purposeinclude, for example, poly(vinylpyrrolidone), polyvinylalcohol,polyethylene oxide, a blend of gelatin and polyvinyl-pyrrolidone,gelatin, glucose, saccharides, povidone, copovidone,poly(vinylpyrrolidone)-poly(vinyl acetate) copolymer and mixturesthereof. The water soluble coating can comprise other pharmaceuticalexcipients that in certain embodiments can alter the way in which thewater soluble coating behaves. The artisan of ordinary skill willrecognize that the above-noted materials include film-forming polymers.The inert water-soluble coat covering the semipermeable wall andblocking the passageway of osmotic dosage forms of the presentinvention, is made of synthetic or natural material which, throughselective dissolution or erosion can allow the passageway to beunblocked thus allowing the process of osmotic delivery to start. Thiswater-soluble coat can be impermeable to a first external fluid, whilebeing soluble in a second external fluid. This property can help toachieve a controlled and selective release of the bupropion hydrobromidesalt from the osmotic dosage form so as to achieve the desired in-vitrorelease rates.

In embodiments where the core of the osmotic dosage form does notcomprise an osmagent, the osmotic dosage forms can comprise an osmoticsubcoat, which can surround the core of the osmotic dosage form. Theosmotic subcoat comprises at least one osmotic agent and at least onehydrophilic polymer. The osmotic subcoat of these embodiments providesfor the substantial separation of the bupropion hydrobromide salt fromthe osmotic agent into substantially separate compartments/layers. Thisseparation can potentially increase the stability of the bupropionhydrobromide salt by reducing possible unfavorable interactions betweenthe bupropion hydrobromide salt and the osmagent, and/or between thebupropion hydrobromide salt and the components of the controlled releasecoat. For example, the osmagent can be hygroscopic in nature, and canattract water that can lead to the degradation of the bupropionhydrobromide salt. Since the osmotic agent of these embodiments can besubstantially separated from the bupropion hydrobromide salt, thebupropion hydrobromide salt can be less prone to degradation from thewater drawn in by the osmagent. The controlled release coat comprises atleast one controlled release polymer and optionally a plasticizer. Thecoated cores of the osmotic dosage form can be filled into capsules, oralternatively can be compressed into tablets using suitable excipients.In these embodiments the osmotic dosage form can utilize both diffusionand osmosis to control drug release, and can be incorporated intosustained release and/or delayed release dosage forms. In addition, incertain embodiments the osmotic pressure gradient and rate of release ofthe bupropion hydrobromide salt can be controlled by varying the levelof the osmotic agent and/or the level of the hydrophilic polymer in theosmotic subcoat, without the need for a seal coat around the osmoticsubcoat.

The hydrophilic polymer used in an osmotic subcoat of certainembodiments of the present invention functions as a carrier for theosmotic agent. In certain embodiments the hydrophilic polymer in theosmotic subcoat does not substantially affect the drug release. In atleast one embodiment, the hydrophilic polymer used in the osmoticsubcoat does not act as a diffusion barrier to the release of thebupropion hydrobromide salt. In at least one embodiment the releaseprofile of the osmotic agent is substantially the same as the releaseprofile of the bupropion hydrobromide salt. Such hydrophilic polymersuseful in an osmotic subcoat of certain embodiments of the presentinvention include by way of example, polyvinyl pyrrolidone, hydroxyethylcellulose, hydroxypropyl cellulose, low molecular weight hydroxypropylmethylcellulose (HPMC), polymethacrylate, ethyl cellulose, and mixturesthereof. In at least one embodiment, the hydrophilic polymer of theosmotic subcoat is a low molecular weight and a low viscosityhydrophilic polymer. A wide variety of low molecular weight and lowviscosity hydrophilic polymers can be used in the osmotic subcoat.Examples of HPMC polymers that can be used in the osmotic subcoatinclude PHARMACOAT® 606, PHARMACOAT® 606G, PHARMACOAT® 603, METHOCEL®E3, METHOCEL® E5, METHOCEL® E6, and mixtures thereof. The hydrophilicpolymer of the osmotic subcoat can be present in an amount of from about1% to about 30% by weight of the osmotic subcoat composition includingall values and ranges therebetween. For example, in certain embodimentsthe hydrophilic polymer is present in an amount of from about 1% toabout 20%, in other embodiments from about 3% to about 10%, and in stillother embodiments about 7% by weight of the osmotic subcoat composition.

In at least one embodiment, the osmotic subcoat comprises about 7%PHARMACOAT® 606, about 1% sodium chloride, and about 92% water, byweight of the osmotic subcoat composition.

One method for producing the osmotic subcoat can be as follows. The atleast one osmotic agent, for example sodium chloride, is dissolved inwater. The solution of osmotic agent and water is then heated to about60° C. The hydrophilic polymer is then added gradually to the solution.A magnetic stirrer can be used to aid in the mixing of the hydrophilicpolymer to the solution of osmotic agent and water. The resultantosmotic subcoating solution can then be used to coat the core of theosmotic dosage form in a fluidized bed granulator, such as a granulatormanufactured by Glatt (Germany) or Aeromatic (Switzerland) to thedesired weight gain. An inlet temperature of from about 10° C. to about70° C. including all values and ranges therebetween, in certainembodiments from about 30° C. to about 55° C., and in at least oneembodiment from about 40° C. to about 45° C.; an outlet temperature offrom about 10° C. to about 70° C. including all values and rangestherebetween, in certain embodiments from about 20° C. to about 45° C.,and in at least one embodiment from about 30° C. to about 35° C.; aproduct temperature of from about 10° C. to about 70° C. including allvalues and ranges therebetween, in certain embodiments from about 20° C.to about 45° C., and in at least one embodiment from about 30° C. toabout 35° C.; an air flow of from about 10 cm/h to about 180 cm/hincluding all values and ranges therebetween; in certain embodimentsfrom about 40 cm/h to about 120 cm/h; and in at least one embodimentfromabout 60 cm/h to about 80 cm/h; an atomizing pressure of from about0.5 bar to about 4.5 bar including all values and ranges therebetween,in certain embodiments from about 1 bar to about 3 bar, and in at leastone embodiment at about 2 bar; a curing temperature of from about 10° C.to about 70° C. including all values and ranges therebetween, in certainembodiments from about 20° C. to about 50° C., and in at least oneembodiment from about 30° C. to about 40° C.; and a curing time of fromabout 5 minutes to about 720 minutes including all values and rangestherebetween; in certain embodiments from about 10 minutes to about 120minutes, and in at least one embodiment at about 30 minutes. Any othertechnology resulting in the coating formulation of the osmotic subcoatconsistent with the objects of the invention can also be used.

The ratio of the components in the core, semipermeable membrane and/orwater-soluble membrane and/or at least one controlled release coatand/or osmotic subcoat as well as the amount of the various membranes orcoats applied can be varied to control delivery of the bupropionhydrobromide salt either predominantly by diffusion across the surfaceof the semipermeable membrane to predominantly by osmotic pumpingthrough the at least one passageway in the semipermeable membrane, andcombinations thereof such that the dosage form can exhibit amodified-release, controlled-release, sustained-release,extended-release, prolonged-release, bi-phasic release, delayed-releaseprofile or a combination of release profiles whereby the in-vitrorelease rates of the bupropion hydrobromide salt is such that afterabout 2 hours from about 0% to about 20% by weight of the bupropionhydrobromide salt is released, after about 4 hours from about 15% toabout 45% by weight of the bupropion hydrobromide salt is released,after about 8 hours, from about 40% to about 90% by weight of thebupropion hydrobromide salt is released, and after about 16 hours, morethan about 80% by weight of the bupropion hydrobromide salt is released.In embodiments where the mode of exit of the bupropion hydrobromide saltcomprises a plurality of pores, the amount of pore forming agentemployed to achievethe desired in-vitro dissolution rates can be readilydetermined by those skilled in the drug delivery art.

In at least one embodiment of the osmotic dosage form, the corecomprises bupropion hydrobromide in an amount of from about 40% to about99% of the core dry weight including all values and ranges therebetween.For example in certain embodiments the core comprises bupropionhydrobromide in an amount of about 40%, about 45%, about 50%, about 55%,about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about90%, about 95% or about 99% of the core dry weight.

In certain embodiments, the core of the osmotic dosage form comprises atleast one means for increasing the hydrostatic pressure inside themembrane or coat. The membrane or coat can be a semipermeable membrane,a controlled release coat, a water-soluble coat, an osmotic subcoat, orany combination thereof. The core of the osmotic dosage form has aneffective osmotic pressure greater than that of the surrounding fluid inthe environment of use so that there is a net driving force for water toenter the core. The at least one means for increasing the hydrostaticpressure inside the membrane or coat can be any material that increasesthe osmotic pressure of the core of the osmotic dosage form. The atleast one means for increasing the hydrostatic pressure inside themembrane or coat can be, for example, the bupropion hydrobromide salt,an osmagent, any material which can interact with water and/or anaqueous biological fluid, swell and retain water within their structure,such as for example an osmopolymer, and any combination thereof. Theosmagent can be soluble or swellable. Examples of osmotically effectivesolutes are inorganic and organic salts and sugars. The bupropionhydrobromide salt can itself be an osmagent or can be combined with oneor more other osmagents, such as for example, magnesium sulfate,magnesium chloride, sodium chloride, lithium chloride, potassiumsulfate, sodium carbonate, sodium sulfite, lithium sulfate, potassiumchloride, calcium carbonate, sodium sulfate, calcium sulfate, potassiumacid phosphate, calcium lactate, d-mannitol, urea, inositol, magnesiumsuccinate, tartaric acid, water soluble acids, alcohols, surfactants,and carbohydrates such as raffinose, sucrose, glucose, lactose,fructose, algin, sodium alginate, potassium alginate, carrageenan,fucoridan, furcellaran, laminaran, hypnea, gum arabic, gum ghatti, gumkaraya, locust bean gum, pectin, starch and mixtures thereof. In certainembodiments the core comprises osmagent in an amount of about 15%, about20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%,about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about85%, about 90%, or about 95% of the core dry weight.

The osmagent useful in certain embodiments of the present invention canbe any agent that can generate an osmotic pressure gradient for thetransport of water from the external environment of use into the osmoticdosage form. Osmagents are also known as osmotically effectivecompounds, osmotic solutes, and osmotic fluid imbibing agents. Osmagentsuseful in certain embodiments of the present invention are soluble inaqueous and biological fluids, such as ionizing compounds, inherentlypolar compounds, inorganic acids, organic acids, bases and salts. In atleast one embodiment the osmagent is a solid and dissolves to form asolution with fluids imbibed into the osmotic dosage form. A widevariety of osagents can be used to provide the osmotic pressure gradientused to drive the bupropion hydrobromide salt from the core of theosmotic dosage form. Examples of inorganic salts useful as osmagentsinclude lithium chloride, lithium sulfate, lithium phosphate, magnesiumchloride, magnesium sulfate, potassium chloride, potassium sulfate,potassium phosphate, potassium acid phosphate, sodium chloride, sodiumsulfate, sodium phosphate, sodium sulfite, sodium nitrate, sodiumnitrite, and mixtures thereof. Examples of salts of organic acids usefulas osagents include sodium citrate, potassium acid tartrate, potassiumbitartrate, sodium bitartrate, and mixtures thereof. Examples ofionizable solid acids useful as osmagents include tartaric, citric,maleic, malic, fumaric, tartronic, itaconic, adipic, succinic, mesaconicacid, and mixtures thereof. Examples of other compounds useful asosmagents include potassium carbonate, sodium carbonate, ammoniumcarbonate, calcium lactate, mannitol, urea, inositol, magnesiumsuccinate, sorbitol, and carbohydrates such as raffinose, sucrose,glucose, lactose, lactose monohydrate, a blend of fructose glucose andmixtures thereof. In at least one embodiment the osmagent is selectedfrom sodium chloride, sodium bromide, sodium bisulfate, potassium acidtartrate, citric acid, mannitol, sucrose and mixtures thereof.Combinations of these osmagents is permissible. The osmagent can bepresent in an amount of from about 0.1% to about 50% of the dosage formweight including all values and ranges therebetween. For example, incertain embodiments the osmagent is present in an amount of from about1% to about 40%, and in other embodiments from about 1% to about 20% ofthe dosage form weight.

In certain embodiments, the at least one means for increasing thehydrostatic pressure can comprise, in addition to an osmagent, anymaterial which can interact with water and/or an aqueous biologicalfluid, swell and retain water within their structure. In certainembodiments where the at least one means for increasing the hydrostaticpressure is an osmopolymer, which can be slightly cross-linked oruncross-linked. The uncross-linked polymers to be used as osmopolymers,when in contact with water and/or aqueous biological fluid, preferablydo not dissolve in water, hence maintaining their physical integrity.Such polymers can be, for example, chosen from the group of polyacrylicacid derivatives (e.g., polyacrylates, poly-methyl methacrylate,poly(acrylic acid) higher alkyl esters, poly(ethylmethacrylate),poly(hexadecyl methacrylate-co-methylmethacrylate),poly(methylacrylate-co-styrene), poly(n-butyl methacrylate),poly(n-butyl-acrylate), poly(cyclododecyl acrylate), poly(benzylacrylate), poly(butylacrylate), poly(secbutylacrylate), poly(hexylacrylate), poly(octyl acrylate), poly(decyl acrylate), poly(dodecylacrylate), poly(2-methyl butyl acrylate), poly(adamantyl methacrylate),poly(benzyl methacrylate), poly(butyl methacrylate), poly(2-ethylhexylmethacrylate), poly(octyl methacrylate), acrylic resins),polyacrylamides, poly(hydroxy ethyl methacrylate), poly(vinyl alcohol),poly(ethylene oxide), poly N-vinyl-2-pyrrolidone, naturally occurringresins such as polysaccharides (e.g., dextrans, water-soluble gums,starches, chemically modified starches), cellulose derivatives (e.g.,cellulose esters, cellulose ethers, chemically modified cellulose,microcrystalline cellulose, sodium carboxymethylcellulose andmethylcellulose), starches, CARBOPOL™, acidic carboxy polymer,CYANAMER™, polyacrylamides, cross-linked water-swellable indene-maleicanhydride polymers, GOOD-RITE™, polyacrylic acid, polyethyleneoxide,starch graft copolymers, AQUA-KEEPS™, acrylate polymer, diestercross-linked polyglucan, and any combination thereof.

In certain embodiments, the core of the osmotic dosage form furthercomprises a means for forcibly dispensing the bupropion hydrobromidesalt from the core to the exterior of the dosage form. The at least onemeans for forcibly dispensing the bupropion hydrobromide salt can be anymaterial which can swell in water and/or aqueous biological fluid andretain a significant fraction of water within its structure, and willnot dissolve in water and/or aqueous biological fluid, a means forgenerating a gas, an osmotically effective solute or any combinationthereof which can optionally be surrounded by a membrane or coatdepending on the particular means used. The membrane or coat can be, forexample, a membrane or coat that is essentially impermeable to thepassage of the bupropion hydrobromide salt, gas and compounds, and ispermeable to the passage of water and/or aqueous biological fluids. Sucha coat or membrane comprises, for example, a semipermeable membrane,microporous membrane, asymmetric membrane, which asymmetric membrane canbe permeable, semipermeable, perforated, or unperforated. In at leastone embodiment, the at least one means for forcibly dispensing thebupropion hydrobromide salt from the core of the osmotic dosage formcomprises a means for generating gas, which means for generating gas issurrounded by, for example, a semipermeable membrane. In operation, whenthe gas generating means imbibes water and/or aqueous biological fluids,the means for generating gas reacts and generates gas, thereby enlargingand expanding the at least one means for forcibly dispensing thebupropion hydrobromide salt unidirectionally or multidirectionally. Themeans for generating a gas comprises any compound or compounds, whichcan produce effervescence, such as for example, at least one solid acidcompound and at least one solid basic compound, which in the presence ofa fluid can react to form a gas, such as for example, carbon dioxide.Examples of acid compounds include, organic acids such as malic,fumaric, tartaric, itaconic, maleic, citric, adipic, succinic andmesaconic, and inorganic acids such as sulfamic or phosphoric, also acidsalts such as monosodium citrate, potassium acid tartrate and potassiumbitartrate. The basic compounds include, for example, metal carbonatesand bicarbonates salts, such as alkali metal carbonates andbicarbonates. The acid and base materials can be used in any convenientproportion from about 1 to about 200 parts of the at least one acidcompound to the at least one basic compound or from about 1 to about 200parts of the at least one basic compound to the at least one acidcompound. The means for generating gas is known.

In at least one embodiment, the at least one means for forciblydispensing the bupropion hydrobromide salt form the core of the osmoticdosage form comprises any material which can swell in water and/oraqueous biological fluid and retain a significant fraction of waterwithin its structure, and will not dissolve in water and/or aqueousbiological fluid, such as for example, a hydrogel. Hydrogels include,for example, lightly cross-linked hydrophilic polymers, which swell inthe presence of fluid to a high degree without dissolution, usuallyexhibiting a 5-fold to a 50-fold volume increase. Non-limiting examplesof hydrogels include poly(hydroxyalkyl methacrylates), poly(acrylamide),poly(methacrylamide), poly(N-vinyl-2-pyrrolidone), anionic and cationichydrogels, polyelectrolyte complexes, a water-insoluble, water-swellablecopolymer produced by forming a dispersion of finely divided copolymersof maleic anhydride with styrene, ethylene, propylene butylene orisobutylene cross-linked with from about 0.001 to about 0.5 moles of apolyunsaturated cross-linking agent per mole of maleic anhydride in acopolymer, water-swellable polymers or N-vinyl lactams, semi-solidcross-linked poly(vinyl pyrrolidone), diester cross-linked polyglucanhydrogels, anionic hydrogels of heterocyclic N-vinyl monomers, ionogenichydrophilic gels, and mixtures thereof. Some of the osmopolymers andhydrogels are interchangeable. Such means can optionally be covered by amembrane or coat impermeable to the passage of the bupropionhydrobromide salt, and compounds, and is permeable to the passage ofwater and/or aqueous biological fluids. Such a coat or membranecomprises, for example, a semipermeable membrane, microporous membrane,asymmetric membrane, which asymmetric membrane can be permeable,semipermeable, perforated, or unperforated.

In at least one other embodiment, the at least one means for forciblydispensing the bupropion hydrobromide salt from the core of the osmoticdosage form comprises at least one osmotically effective solutesurrounded by a membrane or coat impermeable to the passage of thebupropion hydrobromide salt, and compounds, and is permeable to thepassage of water and/or aqueous biological fluids such that theosmotically effective solute exhibits an osmotic pressure gradientacross a membrane or coat. Such coat or membrane comprises, for example,a semipermeable membrane, microporous membrane, asymmetric membrane,which asymmetric membrane can be permeable, semipermeable, perforated,or unperforated. The osmotically effective solutes include, for example,the osmagents described above.

In embodiments of the osmotic dosage form where the means for forciblydispensing the bupropion hydrobromide salt is surrounded by a membraneor coat, at least one plasticizer can be added to the membranecomposition to impart flexibility and stretchability to the membrane orcoat. In embodiments where the means for forcibly dispensing thebupropion hydrobromide salt comprises a means for generating a gas, themembrane or coat preferably is stretchable so as to prevent rupturing ofthe membrane or coat during the period of delivery of the bupropionhydrobromide salt. Methods of manufacturing such a membrane or coat isknown. Plasticizers, which can be used in these embodiments include, forexample, cyclic and acyclic plasticizers, phthalates, phosphates,citrates, adipates, tartrates, sebacates, succinates, glycolates,glycerolates, benzoates, myristates, sulfonamides halogenated phenyls,poly(alkylene glycols), poly(alkylenediols), polyesters of alkyleneglycols, dialkyl phthalates, dicycloalkyl phthalates, diaryl phthalatesand mixed alkyl-aryl phthalates, such as for example, dimethylphthalate, dipropyl phthalate, di(2-ethylhexyl)phthalate, di-isopropylphthalate, diamyl phthalate and dicapryl phthalate; alkyl and arylphosphates, such as for example, tributyl phosphate, trioctyl phosphate,tricresyl phosphate, trioctyl phosphate, tricresyl phosphate andtriphenyl phosphate; alkyl citrate and citrates esters such as tributylcitrate, triethyl citrate, and acetyl triethyl citrate; alkyl adipates,such as for example, dioctyl adipate, diethyl adipate anddi(2-methoxyethyl)adipate; dialkyl tartrates, such as for example,diethyl tartrates and dibutyl tartrate; alkyl sebacates, such as forexample, diethyl sebacate, dipropyl sebacate and dinonyl sebacate; alkylsuccinates, such as for example, diethyl succinate and dibutylsuccinate; alkyl glycolates, alkyl glycerolates, glycol esters andglycerol esters, such as for example, glycerol diacetate, glyceroltriacetate, glycerol monolactate diacetate, methyl phthalyl ethylglycolate, butyl phthalyl butyl glycolate, ethylene glycol diacetate,ethylene glycol dibutyrate, triethylene glycol diacetate, triethyleneglycol dibutyrate, triethylene glycol dipropionate and mixtures thereof.Other plasticizers include camphor, N-ethyl (o- and p-toulene)sulfonamide, chlorinated biphenyl, benzophenone, N-cyclohexyl-p-toluenesulfonamide, substituted epoxides and mixtures thereof.

The at least one means for forcibly dispensing the bupropionhydrobromide salt from the core of certain embodiments of the osmoticdosage form can be located such that it is approximately centrallylocated within the core of the osmotic dosage form and is surrounded bya layer comprising the bupropion hydrobromide salt. Alternatively, thecore of the osmotic dosage form comprises at least two layers in whichthe first layer comprises the bupropion salt, osmagent and/orosmopolymer and optionally at least one pharmaceutically acceptableexcipient adjacent to a second layer comprising the means for forciblydispensing the bupropion hydrobromide salt. Alternatively, the core ofthe osmotic dosage form comprises a multilayered structure in which thelayer comprising the bupropion hydrobromide salt is sandwiched betweentwo layers of the means for forcibly dispensing the bupropionhydrobromide salt from the osmotic dosage form.

Combinations

The present invention also contemplates combinations of the bupropionhydrobromide salt with at least one other drug. For example, acomposition is provided which comprises a first component of bupropionhydrobromide, and a second component of at least one other drug, whereinthe two components are each present in an amount effective in thetreatment of a condition. The present invention further provides amethod for treating a condition, comprising administering to a patientan effective amount of a first component of bupropion hydrobromide incombination with an effective amount of at least one other drug. Theskilled artisan will know or can determine by known methods which drugcombinations are acceptable. Types of drugs that can be selected as thesecond drug include by way of example other depressants, anti-anxietyagents, steroidal and non-steroidal inflammatories, SSRIs, serotoninreceptor agonists, anti-migraine agents, anti-pain agents, anti-emetics,drugs for treating abuse such as nicotine, appetite modulators,anti-virals, vasodilators, and anti-pain agents. For example, the otherdrug can be an antidepressant selected from: monoamine oxidase (MAO)inhibitor, tricyclic antidepressant, serotonin reuptake inhibitor,selective norepinephrine reuptake inhibitors (SNRIs), aminoketones,serotonin antagonists, dopamine reuptake inhibitors, dual reuptakeinhibitors, norepinephrine enhancers, serotonin activity enhancers,dopamine activity enhancers, and combinations thereof. Examples of otherdrugs that can be combined with bupropion hydrobromide includecitalopram, escitalopram, venlafaxine, clozapine, melperone, amperozide,iloperidone, risperidone, quetiapene, olanzapine, ziprasidone,aripiprazole, reboxetine, VIAGRA®, sertraline, paroxetine, fluoxetine,gabapentin, valproic acid, amitriptyline, lofepramine, fluvoxamine,imipramine, mirtazapine, nefazodone, nortriptyline, SAM-E, buspirone,and combinations thereof. In at least one embodiment, a combination ofbupropion hydrobromide and citalopram is provided. In at least one otherembodiment, a combination of bupropion hydrobromide and escitalopram isprovided. In at least one other embodiment a combination of bupropionhydrobromide and venlafaxine is provided. In at least one otherembodiment a combination of bupropion hydrobromide and quetiapene isprovided.

In certain embodiments combination products can be made by providing anovercoat that contains at least one other drug. For example, certainembodiments can include a core that comprises bupropion hydrobromide,wherein the core is substantially surrounded by a controlled releasecoat, which in turn is substantially surrounded by an overcoat thatcontains at least one other drug. In certain embodiments the overcoatprovides an immediate release of the other drug. In addition to theother drug, the overcoat can include at least one low viscosityhydrophilic polymer. The low-viscosity polymer provides for theimmediate release of the other drug from the overcoat. In at least oneembodiment, the low-viscosity polymer used in the overcoat ishydroxypropyl methylcellulose (HPMC). The overcoat can also include alubricant such as talc. For example, such embodiments can provide animmediate release of at least one other drug from the overcoat in afirst phase of drug release, and then a subsequent controlled release ofthe bupropion hydrobromide from the controlled release coated core in asecond phase of drug release.

In addition, combinations of microparticles of the invention each with adifferent functional coating can be combined together in a dosage form.For example, by combining a first group of uncoated, taste-masked orenteric coated microparticles with a second group of delayed orsustained release coated microparticles, a pulsatile drug releaseprofile or chronotherapeutic profile can be achieved. (e.g. see U.S.Pat. No. 5,260,068, U.S. Pat. No. 6,270,805, U.S. Pat. No. 6,926,909,US2002/0098232, US2004/0197405, U.S. Pat. No. 6,635,284, or U.S. Pat.No. 6,228,398).

In other embodiments, the combination can comprise at least 2 differentmicroparticles. For example, the combination can include one group ofmicroparticles that provide for a controlled release of bupropionhydrobromide, and a second group of microparticles that provide for animmediate release of the other drug. The microparticles can be combinedin a capsule formulation.

While only specific combinations of the various features and componentsof the present invention have been discussed herein, it will be apparentto those of skill in the art that desired subsets of the disclosedfeatures and components and/or alternative combinations of thesefeatures and components can be utilized as desired.

As will be seen from the non-limiting examples described below, thecoatings of the invention are quite versatile. For example, the lengthand time for the lagtime can be controlled by the rate of hydration andthe thickness of the controlled release coat. It is possible to regulatethe rate of hydration and permeability of the controlled release coat sothat the desired controlled release profile can be achieved. There is nogeneral preferred controlled release coat thickness, as this will dependon the controlled release profile desired. Other parameters incombination with the thickness of the controlled release coat includevarying the concentrations of one or more of the ingredients of thecontrolled release coat composition, varying the curing temperature andlength of time for curing the coated tablet microparticles, and incertain embodiments, varying the level of osmotic agent. The skilledartisan will know which parameters or combination of parameters tochange for a desired controlled release profile.

Stability Studies

The enhanced stability of the bupropion hydrobromide salt andcompositions containing the bupropion hydrobromide salt, in particularwhen compared to the bupropion hydrochloride salt and compositionscontaining the bupropion hydrochloride salt respectively, is evidentfrom degradation studies performed on the active pharmaceuticalingredient (API), alone, in the presence of excipients and in the formof tablets (e.g. extended release tablets). The results are described ingreater detail in the examples below and for example in U.S. Pat. No.7,241,805, the contents of which are incorporated herein by reference.

A comparison of the stability of several bupropion salts, including thehydrobromide, hydrochloride, maleate, tosylate, fumarate, succinate,tartrate and citrate salts, was performed by placing these salts in bothopen and closed vials in a stability chamber kept at about 40 degrees C.and about 75% relative humidity for various periods of time (e.g. 10days, 13 days, 14 days, 20 days, 24 days, or 32 days). The stability ofthe salts was evaluated based on the formation of the main degradationproducts as determined by HPLC analysis and the % potency (or assay) ofthe API, after specific time periods in the stability chamber. Theeffect of the addition of solvents, such as water, ethanol and isopropylalcohol, was also studied.

The results unexpectedly show that after various periods of time thehydrobromide salt of bupropion, on average, showed the least amount ofdegradation products, particularly when compared to the hydrochloridesalt. Accordingly the bupropion hydrobromide salt showed greaterstability than the hydrochloride salt.

Further stability tests were performed by directly comparing bupropionhydrobromide and bupropion hydrochloride salts in forced degradationstudies. These studies were performed in closed bottles in a stabilitychamber kept at about 40 degrees C. and about 75% relative humidity. Atspecified times, the material in the bottles was analyzed for thepresence of degradation products and % potency (% assay). It wasunexpectedly found that the amount of impurities was generally lower andthe % potency was generally higher for the bupropion hydrobromide saltwhen compared to the bupropion hydrochloride salt.

Forced degradation studies were also performed on bupropion hydrobromideand bupropion hydrochloride API's in the presence of standard excipientsused in pharmaceutical formulations. The amount of the main degradationproducts was observed at about 24 and about 48 hours after treatment atabout 55° C., at about 55° C. and 100% relative humidity, and at about105° C. Once again, it was unexpectedly found that the bupropionhydrobromide salt showed the lowest amount of degradation (as determinedby the formation of bupropion degradation impurities) under theseconditions.

The stability of the tablet formulations of bupropion hydrobromide andbupropion hydrochloride salts was also compared. With both salts, asingle coated tablet having a controlled release coat (e.g. ETHOCEL® or“EC” coat), as well as a double-coated tablet (with a controlled releasecoat and a moisture barrier coat) were evaluated. The tablets wereplaced individually on an open dish, and exposed to the acceleratedconditions of about 40° C. and about 75% relative humidity in astability chamber. After 13 days and 20 days, the samples were assayedand impurity analysis was performed. For the single coated bupropionhydrochloride tablets, the main degradation impurities 3-CBZ and 852U77were about 0.12% and about 0.38% respectively, whereas, for thebupropion hydrobromide tablets, these values were about 0.07% and about0.49% respectively. The other degradation impurities and the totalunknowns were very similar for both products; however, the assay valuefor the hydrobromide product was higher than the hydrochloride. Thedifference in the assay and the impurity levels were more significant inthe double coated tablets products. For the same period of the study theassay of the bupropion hydrochloride was lower (about 95.5% compared toabout 98.6% for bupropion hydrobromide) and the level of the degradationand total unknowns were higher (3-CBZ: about 0.28%; 852U77: about 1.23%;827U76: about 0.10%; and total about 1.73%) than the bupropionhydrobromide (3-CBZ: about 0.12%, 852U77: about 0.41%, 827U76: about0.05%; and total about 0.75%).

The stability studies performed herein have demonstrated the unexpectedenhanced stability of bupropion hydrobromide, in particular whencompared to bupropion hydrochloride. This enhanced stability is seenwith the API form alone, the API form plus excipients, and the extendedrelease and enhanced absorption tablets. The enhanced stability ofpharmaceutical formulations comprising bupropion hydrobromide willprovide enhanced shelf life and an ability to withstand storage athigher temperatures and humidity levels when compared with bupropionhydrochloride formulations.

Additional Embodiments

Further embodiments of the invention described herein and enabled by thepresent description include the following:

Certain embodiments include bupropion hydrobromide and3′-chloro-2-bromo-propiophenone. 3′-chloro-2-bromo-propiophenone is animpurity associated with the preparation of bupropion hydrobromide. Incertain embodiments, 3′-chloro-2-bromo-propiophenone is present in anamount that is non-genotoxic; or in an amount that would result in adaily exposure of not more than (“NMT”) about 1.5 μg/day in the drugproduct. Certain embodiments contain less than about 1.5 μg of3′-chloro-2-bromo-propiophenone. For example in certain embodiments the3′-chloro-2-bromo-propiophenone impurity is present in an amount of lessthan about 1.5 μg, 1.4 μg, 1.3 μg, 1.2 μg, 1.1 μg, 1.0 μg, 0.9 μg, 0.8μg, 0.7 μg, 0.6 μg, 0.5 μg, 0.4 μg, 0.3 μg, 0.2 μg, 0.1 μg, 0.09 μg,0.08 μg, 0.07 μg, 0.06 μg, 0.05 μg, 0.04 μg, 0.03 μg, 0.02 μg, or 0.01μg, including all values and subranges therebetween. In at least oneembodiment the 3′-chloro-2-bromo-propiophenone impurity is present inundetectable amounts wherein the limit of detection is 1.0 μg, or 1 ppm.

In certain embodiments the 3-chlorobenzoic acid degradation product islimited in the drug product to about 0.7% or less. In at least oneembodiment the 3-chlorobenzoic acid degradation product is limited inthe composition to about 0.5% or less. In at least one furtherembodiment the 3-chlorobenzoic acid degradation product is limited inthe composition to about 0.3% or less.

In certain embodiments the moisture content in the drug product islimited to not more than about 2.0%. In certain embodiments the moisturecontent is limited to not more than about 2.0% after a storage time ofabout 1 minute when stored in a closed container using a Karl Fischerapparatus and UPS Method 1. For example in certain embodiments themoisture content after a storage time of about 1 minute when stored in aclosed container using a Karl Fischer apparatus, and USP Method 1, isless than about 2.0%, 1.9%, 1.8%, 1.7%, 1.6%, 1.5% 1.4%, 1.3%, 1.2%,1.1%, 1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1%,including all values and subranges therebetween.

In another embodiment there is a tablet comprising (i) a core and (ii) acontrolled release coat, said core comprising:

(a) bupropion HBr;(b) binder (e.g. polyvinyl alcohol); and(c) lubricant (e.g. glyceryl behenate—Compritol® 888); said controlledrelease coat (e.g., “SMARTCOAT”) comprising:(d) water-insoluble water-permeable film-forming polymer (e.g. ethylcellulose grade PR 100);(e) plasticizer (e.g. polyethylene glycol 4000, dibutyl sebacate, or amixture thereof);(f) water-soluble polymer (e.g. polyvinylpyrrolidone—Povidone® USP);wherein in the controlled release coat the ratio of (d):(e):(f)=fromabout 3:1:4 to about 5:1:2; or from about 7:2:6 to about 19:5:18; orabout 13:4:12; or about 13:6:16;the tablet optionally further comprising a moisture barrier coat;said optional moisture barrier coat comprising:(g) enteric polymer (e.g. an acrylic polymersuch as methacrylic acidcopolymer type C—Eudragit® L30 D-55);(h) permeation enhancer (e.g. silicon dioxide—Syloid® 244FP); and(i) plasticizer (optional)—(e.g. mixture of triethyl citrate andpolyethylene glycol 4000-Carbowax® 4000).

In another embodiment there is a once-daily modified releasepharmaceutical composition comprising 522 mg of bupropion hydrobromide,said composition providing an in-vivo plasma profile selected from:

Mean Tmax of from about 2 hours to about 7 hours;Mean Cmax of from about 113 ng/ml to about 239 ng/ml;Mean Cmin of from about 18 ng/ml to about 44 ng/ml; andMean AUC0-t of from about 1236 ng-hr/ml to about 2224 ng-hr/ml.

In another embodiment there is a once-daily modified releasepharmaceutical composition comprising 348 mg of bupropion hydrobromide,said composition providing an in-vivo plasma profile selected from:

Mean Tmax of from about 2 hours to about 7 hours;Mean Cmax of from about 96 ng/ml to about 172 ng/ml;Mean Cmin of from about 17 ng/ml to about 36 ng/ml; andMean AUC0-t of from about 1063 ng-hr/ml to about 1755 ng-hr/ml.

In another embodiment there is a once-daily modified releasepharmaceutical composition comprising bupropion hydrobromide, saidcomposition providing a mean Tmax of from about 2 hours to about 7hours.

In another embodiment there is a once-daily modified releasepharmaceutical composition comprising bupropion hydrobromide, saidcomposition providing a mean Tmax that is substantially equivalent tothat of a once-daily modified release pharmaceutical compositioncomprising bupropion hydrochloride.

In another embodiment there is a once-daily modified releasepharmaceutical composition comprising bupropion hydrobromide, saidcomposition providing a mean Tmax that is from about 80% to about 125%of that of a once-daily modified release pharmaceutical compositioncomprising bupropion hydrochloride.

In another embodiment there is a once-daily modified releasepharmaceutical composition comprising bupropion hydrobromide, saidcomposition providing a mean Cmax that is substantially equivalent tothat of a once-daily modified release pharmaceutical compositioncomprising bupropion hydrochloride.

In another embodiment there is a once-daily modified releasepharmaceutical composition comprising bupropion hydrobromide, saidcomposition providing a mean Cmax that is from about 80% to about 125%of that of a once-daily modified release pharmaceutical compositioncomprising bupropion hydrochloride.

In another embodiment there is a once-daily modified releasepharmaceutical composition comprising bupropion hydrobromide, saidcomposition providing a mean Cmin that is substantially equivalent tothat of a once-daily modified release pharmaceutical compositioncomprising bupropion hydrochloride.

In another embodiment there is a once-daily modified releasepharmaceutical composition comprising bupropion hydrobromide, saidcomposition providing a mean Cmin that is from about 80% to about 125%of that of a once-daily modified release pharmaceutical compositioncomprising bupropion hydrochloride.

In another embodiment there is a once-daily modified releasepharmaceutical composition comprising bupropion hydrobromide, saidcomposition providing a mean AUC0-t that is substantially equivalent tothat of a once-daily modified release pharmaceutical compositioncomprising bupropion hydrochloride.

In another embodiment there is a once-daily modified releasepharmaceutical composition comprising bupropion hydrobromide, saidcomposition providing a mean AUC0-t that is from about 80% to about 125%of that of a once-daily modified release pharmaceutical compositioncomprising bupropion hydrochloride.

In another embodiment there is a modified release pharmaceuticalcomposition comprising:

a core comprising a therapeutically effective amount of bupropionhydrobromide; anda controlled release polymeric coat comprising a water-insoluble polymerand a water-soluble polymer;wherein said coat surrounds at least a part of said core; andwherein the amount of bupropion hydrobromide released at a time pointfrom about 0 hours to about 16 hours, in the presence of at least 5%ethanol, using USP Apparatus I at 75 rpm and 37±0.5° C., is less thanthe amount of bupropion hydrobromide released at the same time point in0.1 N HCl using USP Apparatus I at 75 rpm and 37±0.5° C.

In another embodiment there is a modified release pharmaceuticalcomposition comprising:

a core comprising a therapeutically effective amount of bupropionhydrobromide; anda controlled release polymeric coat comprising a water-insoluble polymerand a water-soluble polymer;wherein said coat surrounds at least a part of said core; andwherein the amount of bupropion hydrobromide released at a time pointfrom about 0 hours to about 16 hours, in the presence of at least 5%ethanol, using USP Apparatus I at 75 rpm and 37±0.5° C., is less thanabout 125% of the amount of bupropion hydrobromide released at the sametime point in 0.1 N HCl using USP Apparatus I at 75 rpm and 37±0.5° C.

In another embodiment there is a modified release pharmaceuticalcomposition comprising:

a core comprising a therapeutically effective amount of bupropionhydrobromide; anda controlled release polymeric coat comprising a water-insoluble polymerand a water-soluble polymer;wherein said coat at least partially surrounds said core; andwherein dose dumping does not occur in the presence of 0.1 N HCl with40% EtOH.

In another embodiment there is a method of reducing dose dumpingcomprising administering to a subject a modified release pharmaceuticalcomposition comprising:

a core comprising a therapeutically effective amount of bupropionhydrobromide; anda controlled release polymeric coat comprising a water-insoluble polymerand a water-soluble polymer;wherein said coat at least partially surrounds said core.

In another embodiment there is a pharmaceutical composition comprising522 mg of bupropion hydrobromide, said composition providing an in-vivoplasma profile selected from:

Mean Tmax of from about 2 hours to about 7 hours;Mean Cmax of from about 115 ng/ml to about 235 ng/ml;Mean Cmin of from about 20 ng/ml to about 40 ng/ml; andMean AUC0-24 hr of from about 1240 ng-hr/ml to about 2220 ng-hr/ml.

In another embodiment there is a pharmaceutical composition comprising522 mg of bupropion hydrobromide, said composition providing an in-vivoplasma profile selected from:

Mean Tmax of about 4 hours;Mean Cmax of less than about 200 ng/ml; andMean AUC0-24 hr of more than about 2000 ng-hr/ml.

In another embodiment there is a once-daily modified releasepharmaceutical composition comprising bupropion hydrobromide, saidcomposition providing a mean Tmax that is substantially equivalent tothat of the same once-daily modified release pharmaceutical compositioncomprising bupropion hydrochloride instead of bupropion hydrobromide.

In another embodiment there is a once-daily modified releasepharmaceutical composition comprising bupropion hydrobromide, saidcomposition providing a mean Tmax that is from about 80% to about 125%of that of the same once-daily modified release pharmaceuticalcomposition comprising bupropion hydrochloride instead of bupropionhydrobromide.

In another embodiment there is a modified release tablet comprising

(i) a core comprising(a) a therapeutically effective amount of bupropion hydrobromide;(b) a binder; and(c) a lubricant; and(ii) a control-releasing polymeric coat at least partially surroundingsaid core;wherein said modified release tablet provides for the controlled releaseof said bupropion hydrobromide from said modified release tablet over aperiod of about 24 hours; andwherein said modified release tablet has improved stability whencompared to an otherwise similar or identical modified release tabletcomprising an equivalent molar amount of bupropion hydrochloride insteadof bupropion hydrobromide, when each are stored for at least about 12months at about 25° C. and at about 60% relative humidity.

In another embodiment there is a modified release bupropion hydrobromidetablet suitable for oral administration comprising

(i) a core comprising(a) a therapeutically effective amount of bupropion hydrobromide;(b) a binder; and(c) a lubricant;(ii) a controlled release polymeric coat which at least partiallysurrounds said core; and(iii) a degradation product chosen from 3-chlorobenzoic acid, 827U76,20U78, 852U77, and mixtures thereof;wherein said modified release bupropion hydrobromide tablet containsless of said degradation product as compared to an otherwise similar oridentical modified release tablet containing an equivalent molar amountof bupropion hydrochloride instead of bupropion hydrobromide;when the modified release bupropion hydrobromide tablet and theotherwise similar or identical modified release tablet containingbupropion hydrochloride are each are stored for at least about 12 monthsat 25° C. and 60% relative humidity after tablet formulation.

In another embodiment there is a modified release tablet comprising:

a therapeutically effective amount of bupropion hydrobromide;wherein at about 12 months after formulation of said modified releasetablet, at about 37±0.5° C., from about 0% to 40% of said bupropionhydrobromide is released after 2 hours; fromabout 40% to about 75% of said bupropion hydrobromide is released after4 hours; not less than about 75% of said bupropion hydrobromide isreleased after 8 hours; and not less than about 85% of said bupropionhydrobromide is released after 16 hours, in 900 ml of 0.1 N HCl usingUSP Type 1 apparatus with a rotational speed of 75 rpm.

In another embodiment there is a modified release pharmaceuticalcomposition comprising:

(i) a core comprising a therapeutically effective amount of bupropionhydrobromide; and(ii) a controlled release polymeric coat comprising a water-insolublepolymer and a water-soluble polymer;wherein said coat at least partially surrounds said core; andwherein said composition is resistant to alcohol-induced dose dumping.

In another embodiment there is a modified release pharmaceuticalcomposition comprising:

(i) a core comprising a therapeutically effective amount of bupropionhydrobromide; and(ii) a controlled release polymeric coat comprising a water-insolublepolymer and a water-soluble polymer;wherein said coat at least partially surrounds said core; andwherein the rate of release of bupropion hydrobromide in dissolutionmedia containing alcohol is slower than the rate of release of bupropionhydrobromide in dissolution media not containing alcohol.

In another embodiment there is a modified release pharmaceuticalcomposition comprising:

(i) a core comprising a therapeutically effective amount of bupropionhydrobromide; and(ii) a controlled release polymeric coat comprising a water-insolublepolymer and a water-soluble polymer;wherein said coat at least partially surrounds said core; andwherein the amount of bupropion hydrobromide released at a time pointfrom about 0 hours to about 16 hours, in dissolution media comprisingabout 40% EtOH and 60% 0.1N HCl, using USP Apparatus Type 1 at 75 rpm,is not more than the amount of bupropion hydrobromide released at thesame time point in dissolution media comprising about 100% 0.1N HClusing USP Apparatus Type 1 at 75 rpm.

In another embodiment there is a modified release pharmaceuticalcomposition comprising:

(i) a core comprising a therapeutically effective amount of bupropionhydrobromide; and(ii) a controlled release polymeric coat comprising a water-insolublepolymer and a water-soluble polymer;wherein said coat at least partially surrounds said core; andwherein the amount of bupropion hydrobromide released at a time pointfrom about 0 minutes to about 120 minutes, in dissolution mediacomprising about 40% EtOH and 60% 0.1N HCl, using USP Apparatus Type 1at 75 rpm, is not more than the amount of bupropion hydrobromidereleased at the same time point in dissolution media comprising about100% 0.1N HCl using USP Apparatus Type 1 at 75 rpm.

In another embodiment there is a method of resisting alcohol-induceddose dumping of bupropion hydrobromide comprising administering to asubject a modified release pharmaceutical composition, said compositioncomprising:

(i) a core comprising a therapeutically effective amount of bupropionhydrobromide; and(ii) a controlled release polymeric coat comprising a water-insolublepolymer and a water-soluble polymer;wherein said coat at least partially surrounds said core.

In another embodiment there is a method of treating a subject at risk ofalcohol-induced dose dumping of bupropion hydrobromide and in need ofbupropion treatment, the method comprising administering to a subject amodified release pharmaceutical composition, said compositioncomprising:

(i) a core comprising a therapeutically effective amount of bupropionhydrobromide; and(ii) a controlled release polymeric coat comprising a water-insolublepolymer and a water-soluble polymer;wherein said coat at least partially surrounds said core.

In another embodiment there is a composition comprising bupropionhydrobromide and 3′-chloro-2-bromo-propiophenone.

In another embodiment there is a composition comprising bupropionhydrobromide and less than about 1.5 μg of3′-chloro-2-bromo-propiophenone.

In another embodiment there is a composition comprising bupropionhydrobromide and less than about 1.0 μg of3′-chloro-2-bromo-propiophenone.

In another embodiment there is a modified release composition comprisingbupropion hydrobromide wherein the moisture content is not more thanabout 2.0% in said composition after a storage time of about 1 minute,when stored in a closed container using a Karl Fischer apparatus, USPMethod 1.

In another embodiment there is a composition comprising bupropionhydrobromide and at least one pharmaceutically acceptable excipient,wherein the amount of bupropion hydrobromide is chosen from 174 mg, 348mg and 522 mg.

In another embodiment there is a modified release tablet comprisingbupropion hydrobromide and at least one pharmaceutically acceptableexcipient, wherein the amount of bupropion hydrobromide is chosen from174 mg, 348 mg and 522 mg.

In another embodiment there is a modified release tablet comprisingbupropion hydrobromide and at least one pharmaceutically acceptableexcipient, wherein the amount of bupropion hydrobromide is chosen from174 mg, 348 mg and 522 mg; and wherein the bupropion hydrobromide iscontained within a core of the tablet further comprising a controlledrelease coating over the core.

In another embodiment there is a composition comprising at leastbupropion hydrobromide in the concentration specified in one of A, B,and C in the following Table admixed with one or more additionalcomponents listed in A, B and C in the following Table:

Component A B C Bupropion 174 mg   348 mg  522 mg Hydrobromide PolyvinylAlcohol 5.8 mg 11.6 mg 22.5 mg Glyceryl Behenate 5.8 mg 11.6 mg 22.5 mgTarget Core Tablet 185.6 mg  371.2 mg   567 mg Weight (mg)Ethylcellulose 100, NF 15.4 mg  16.4 mg 18.13 mg  Povidone (K-90) 9.5 mg10.2 mg 21.87 mg  Polyethylene Glycol, 3.4 mg  3.7 mg 5.33 mg 4000Dibutyl Sebacate 1.7 mg  1.8 mg 2.67 mg (DBS) Target Coating Weight +30mg   +32 mg  +48 mg Gain (mg) Carnauba Wax Trace Amount Trace Amount N/ADenatured Ethyl Evaporated Off Evaporated Off Evaporated Off Alcohol,200 proof Ethyl Alcohol, Evaporated Off Evaporated Off Evaporated Off190 proof Purified Water Evaporated Off Evaporated Off Evaporated OffOpacode R Black Ink Trace Amount Trace Amount Trace Amount IsopropylAlcohol, None None None 99% Final Printed Tablet 216 mg 403 mg 615 mgWeight (mg)

In another embodiment there is a composition comprising at least about522 mg of bupropion hydrobromide and at least one pharmaceuticallyacceptable excipient. In other aspects of this embodiment thecomposition is in tablet form. In other aspects of this embodiment thecomposition is a modified release formulation. In other aspects of thisembodiment the composition is in tablet form and the bupropionhydrobromide is contained within a core of the tablet further comprisinga coating over the core. In other aspects of this embodiment the coatingis a controlled release coating.

In at least one embodiment the bupropion hydrobromide 174 mg tabletcomposition releases bupropion hydrobromide in a first dissolutionmedium consisting of ethanol (5%-40%) and 0.1N HCl, at a rate that isless than or equal to about 1.1 times the rate of release of bupropionhydrobromide from the identical bupropion hydrobromide 174 mg tabletcomposition in a second dissolution medium consisting of 0.1N HCl(100%), measured over a time period of at least from 0 to 2 hours,measured using a USP Apparatus I at 75 rpm and at 37° C. See for exampleU.S. patent application Ser. No. 11/930,644 (Pub. No. 2008-0274181), thecontents of which are incorporated herein by reference. In at least oneembodiment the bupropion hydrobromide 174 mg tablet composition releasesbupropion hydrobromide in a first dissolution medium consisting ofethanol (40%) and 0.1N HCl, at a rate that is less than the rate ofrelease of bupropion hydrobromide from the identical bupropionhydrobromide 174 mg tablet composition in a second dissolution mediumconsisting of 0.1N HCl (100%), measured over a time period of at leastfrom 0 to 24 hours, measured using a USP Apparatus I at 75 rpm and at37° C.

In at least one embodiment the bupropion hydrobromide 174 mg tabletcomposition releases bupropion hydrobromide in a first dissolutionmedium consisting of ethanol (5%-40%) and 0.1N HCl at a rate that isless than or equal to about 1.1 times the rate of release of bupropionhydrobromide from the identical bupropion hydrobromide 174 mg tabletcomposition in a second dissolution medium consisting of 0.1N HCl(100%), measured over a time period of at least from 0 to 2 hours,measured using a USP Apparatus I at 75 rpm and at 37° C.

In at least one embodiment the bupropion hydrobromide 348 mg tabletcomposition releases bupropion hydrobromide in a first dissolutionmedium consisting of ethanol (5%-40%) and 0.1N HCl at a rate that isless than or equal to about 1.1 times the rate of release of bupropionhydrobromide from the identical bupropion hydrobromide 348 mg tabletcomposition in a second dissolution medium consisting of 0.1N HCl(100%), measured over a time period of at least from 0 to 2 hours,measured using a USP Apparatus I at 75 rpm and at 37° C.

In at least one embodiment the bupropion hydrobromide 522 mg tabletcomposition releases bupropion hydrobromide in a first dissolutionmedium consisting of ethanol (40%) and 0.1N HCl (60%) at a rate that isless than the rate of release of bupropion hydrobromide from theidentical bupropion hydrobromide 522 mg tablet composition in a seconddissolution medium consisting of 0.1N HCl (100%), measured over a timeperiod of at least from 0 to 16 hours, measured using a USP Apparatus Iat 75 rpm and at 37° C.

In at least one embodiment the bupropion hydrobromide 522 mg tabletcomposition releases bupropion hydrobromide in a first dissolutionmedium consisting of ethanol (5%-40%) and 0.1N HCl, at a rate that isless than or equal to the rate of release of bupropion hydrobromide fromthe identical bupropion hydrobromide 522 mg tablet composition in asecond dissolution medium consisting of 0.1N HCl (100%), measured over atime period of at least from 0 to 2 hours, measured using a USPApparatus I at 75 rpm and at 37° C.

In at least one embodiment a bupropion hydrobromide 174 mg tabletcomposition releases bupropion hydrobromide in a first dissolutionmedium consisting of ethanol (40%) and 0.1N HCl (60%), at a rate that isless than the rate of release of bupropion hydrobromide from theidentical bupropion hydrobromide 174 mg tablet composition in a seconddissolution medium consisting of 0.1N HCl (100%), measured over a timeperiod of at least from 0 to 24 hours, measured using a USP Apparatus Iat 75 rpm and at 37° C. In at least one embodiment a bupropionhydrobromide 174 mg tablet releases bupropion hydrobromide in adissolution medium consisting of ethanol (40%) and 0.1N HCl (60%), at arate that is less than the rate of release of bupropion hydrochloridefrom a bupropion hydrochlroide 150 mg tablet having the identicalpolymeric controlled release coat composition used in the bupropionhydrobromide 174 mg tablet, in the identical dissolution mediumconsisting of ethanol (40%) and 0.1N HCl (60%), measured over a timeperiod of at least from 0 to 16 hours, measured using a USP Apparatus Iat 75 rpm and at 37° C.

In at least one embodiment a bupropion hydrobromide 174 mg tabletcomposition releases bupropion hydrobromide in a first dissolutionmedium consisting of ethanol (40%) and 0.1N HCl (60%), at a rate that isless than the rate of release of bupropion hydrobromide from theidentical bupropion hydrobromide 174 mg tablet composition in a seconddissolution medium consisting of 0.1N HCl (100%), measured over a timeperiod of at least from 0 to 2 hours, measured using a USP Apparatus Iat 75 rpm and at 37° C. In at least one embodiment a bupropionhydrobromide 174 mg tablet releases bupropion hydrobromide in adissolution medium consisting of ethanol (40%) and 0.1N HCl (60%), at arate that is less than the rate of release of bupropion hydrochloridefrom a bupropion hydrochlroide 150 mg tablet having the identicalpolymeric controlled release coat composition used in the bupropionhydrobromide 174 mg tablet, in the identical dissolution mediumconsisting of ethanol (40%) and 0.1N HCl (60%), measured over a timeperiod of at least from 0 to 2 hours, measured using a USP Apparatus Iat 75 rpm and at 37° C.

The examples below are non-limiting and are representative of variousaspects of certain embodiments of the present invention.

EXAMPLES Example 1 Preparation of Bupropion HBR Salt

Bupropion HBr salt was prepared according to the method shown in Scheme1:

(a) Bromination and Condensation Reactions

3-Chloro-propiophenone starting material was brominated in methylenechloride by dropping bromine under controlled conditions. On reactioncompletion the mother liquor was worked up and then the second reactionwas executed by transferring the bromoderivative solution onto thetert-butylamine. The second substitution reaction (the tert-butylamineamino-group substitutes the bromine atom) forms the final bupropionmolecule. After work up of the mother liquor, a bupropion toluenesolution was obtained. The solvent was evaporated and bupropion wasdissolved in isopropanol. From the isopropanol solution, thehydrobromide was precipitated with hydrogen bromide gas. Onprecipitation completion, the product was centrifuged, washed withisopropanol and dried under vacuum. On dryer discharge approval it wasdischarged in Kraft drums within double polyethylene bags.

In the last finishing step, the above intermediate was sieved to obtainthe Final Release which was packed in Kraft drums within doublepolyethylene bags.

Elemental analysis of the bupropion HBr was carried out using a FisonsElemental Analyser EA 1108. The results were consistent with themolecular formula of bupropion HBr.

Example 2 Bupropion HBr Extended Release (XL) Tablets

The aim of this example was to describe the development of bupropion HBrXL (174 and 348 mg). Granulation, tabletting and coating procedures areall described thoroughly in this example. In-vitro testing was conductedon the cores, the ethylcellulose coated cores and the final coatedtablets in order to determine which formulation gave the desiredresults. From their structural formulae, it is observable that thedifference between bupropion HCl and bupropion HBr is the salt. This, ofcourse, results in a different molecular weight. However, thesedifferences were taken into account in the present study, andmodifications were made in order to obtain in-vitro correlation resultsto the bupropion HCl using dissolution studies.

It was previously observed that when 150 mg of bupropion HCl was testedfor its release of bupropion, the base value that was released was 130mg. However, when 150 mg of bupropion HBr was tested, the base valuereleased was only 112 mg. Thus, the amount of bupropion HBr had to beincreased in order to increase the base value from 112 mg to 130 mg,which was the target. Studies showed that 174 mg of bupropion HBr gave abase value release of 130 mg and is therefore why 174 mg was used asopposed to 150 mg bupropion HBr.

Bupropion HBr XL—Granulation Process

A summary of the manufacturing process used for the preparation ofbupropion HBr XL tablets is shown in FIG. 1.

The following materials were used in the granulation of the immediaterelease core of the bupropion HBr EA tablets: bupropion HBr, polyvinylalcohol (PVA) and purified water. Once granulated, lubricant (COMPRITOL®888) was added to complete the formulation. Each Trial was divided into5 parts. The percentage of API in each formulation was 93.75%; thepercentage of PVA in each formulation was 3.125%. A summary of thebreakdown of each trial per part is described in Table 1.

The PVA was dissolved into the purified water using a magnetic stirrerand a clear colourless solution was made.

The NIRO Fluid Bed was used to granulate the bupropion HBr Granules withthe PVA solution in a process known as wet massing. FIG. 2 shows asummary of the granulation procedure.

The Bupropion HBr was loaded into the fluid bed and granulation wasinitiated. The specifications that were used as guidelines are listed inTable 2.

Loss on Drying was determined after each granulation using the MoistureAnalyzer. A 1 g sample was taken and loaded into the moisture analyzer.The sample ran for 5 minutes at a temperature of 105° C.

Upon completion of each batch part's granulation, the five parts werecombined together. They were hand screened using Mesh No. 14 (1.4 mm)and any oversized granulation was passed through the Comil fitted with a2 mm screen.

COMPRITOL® 888 was used as a lubricant in the formulation. The screenedbupropion HBr granules and the COMPRITOL® 888 were loaded into theV-blender and were blended for 5 minutes. The COMPRITOL® 888 made up3.125% of the formulation. The final granule batch size is described inTable 3.

Bupropion HBr XL—Tabletting Process

The Beta Press was used to compress the Bupropion HBr tablets. Dependingon the dose of the tablet, 174 mg or 348 mg, different tooling sets wereused. The 7 mm punches were used to compress the 174 mg tablets and 9 mmand 10 mm punches were used to compress the 348 mg tablets. Tooling waspolished prior to each run.

The tablet weights were determined as being 185.6 mg for the 174 mg dosetablets and 371.2 mg for the 348 mg dose tablets. These adjustments totablet weight were made in order to compensate for the fact thatbupropion HBr was being used in place of bupropion HCl.

The individual tablet weights had a control limit of ±5%, and theaverage tablet weight had a control limit of ±3% (using ten tablets).

A hardness tester was used to determine the load required todiametrically break the tablets (crushing strength) into two equalhalves. A predetermined range set the specifications for hardness, whichwas 6.0-12.0 SC for both the 174 mg and 348 mg tablets.

Friability was determined using tablets that equaled a weight of 6.5 gin a friability tester for 4 minutes at 25 rpm. Tablets were de-dustedbefore and after testing. A weight loss of less than 0.8% was used asthe criteria in order to accept or reject a batch.

Table 4 summarizes the specifications of the tablet press set-up. Allthe specifications were kept within the range and at the setting thatwas assigned, throughout all of the batches. Table 5 summarizes thespecifications that were kept constant throughout the compression of allthe batches.

The flow chart shown in FIG. 2 describes the steps that led up to andincluding the tabletting process. FIG. 3 shows a summary of thetabletting procedure.

Bupropion HBr XL—Coating Process

A summary of the coating process used for the coating of the BupropionHBr XL tablets is shown in FIG. 4. The first coat is an ethylcellulose(e.g. ETHOCEL®) coat that controls the release, which is followed by afinal coat that acts as a moisture barrier. For the ethylcellulosecoating and final coating of the Bupropion HBr XL tablets, the 15 inchesO′Hara Labcoat II System was used. An attached spraying nozzle and apropeller mixer were also used.

Several ethylcellulose coating solutions were developed and used to coatthe Bupropion HBr tablets. The ethylcellulose coating layer was placedon the tablets containing one of the formulations listed in Table 6.

In formulation 1, ethyl Alcohol 95% and IPA 99% were combined togetherin a stainless steel container. While stirring, PEG 4000 was added andallowed to dissolve. Once dissolved, ethylcellulose (e.g. ETHOCEL®) wasadded and left to stir for 30 minutes. Then, Povidone was added to thesolution and was mixed for an overnight period (15-20 hours).

In formulation 2, PEG4000 was placed into a beaker with the DibutylSebacate and was stirred until it dissolved. Ethyl Alcohol 95% was addedaccordingly in order to allow the PEG 4000 to completely dissolve. In aseparate stainless steel container, the remaining Ethyl Alcohol 95% wasplaced and, while being stirred, ethylcellulose was added and stirredfor 30 minutes. Following that, Povidone was added and allowed to stirfor an overnight period (15-20 hours).

In formulation 3, Ethyl Alcohol 95% was placed in a stainless steelcontainer. While stirring, PEG 4000 was added and allowed to dissolve.Once dissolved, ethylcellulose was added and left to stir for 30minutes. Then, Povidone was added to the solution and was mixed for anovernight period (15-20 hours).

Two Final coating solutions were developed and used to coat theBupropion HBr tablets after they had been first coated with theethylcellulose coat.

One of the following formulations shown in Table 7 was used to coat thetablets with a final coat.

In Formulation A, the purified water was placed in a glass beaker andChroma-Tone DEB 5156-CLE was added and allowed to mix for 15 minutes.The EUDRAGIT® was passed through a Mesh screen (no. 60) prior to use.Following this, the EUDRAGIT® was added to the beaker and was stirredfor 15 more minutes.

In Formulation B, part 1 of the Purified Water was placed into a glassbeaker and PEG 4000 was added to it and allowed to mix until it wascompletely dissolved (5 minutes). The Triethyl Citrate was then addedand left to mix for another 5 minutes. Once dissolved, the solution wasthen added to the EUDRAGIT® Suspension and left to stir for 45 minutes.The EUDRAGIT® was passed through a Mesh screen (no. 60) prior to use. Ina separate beaker, part 2 of the purified water was added to the SYLOID®244FP and mixed until it was completely dissolved (10 minutes). Finallythe SYLOID® Suspension was added to the EUDRAGIT® Suspension and left tostir for another 10 minutes.

Table 8 summarizes the specifications that were monitored in theethylcellulose coating process and their ranges.

Table 9 summarizes the specifications that were monitored in the finalcoating process and their ranges.

In-vitro Studies on the Bupropion HBr Cores

Dissolution was performed on the Bupropion HBr cores, on the differentweight gains of ethylcellulose coated cores and on the different weightgains of final coated tablets. USP-1 method was used to conduct thesestudies. The dissolution test was performed using 900 mL of 0.1N HCl andat a speed of 75 rpm. Samples were taken at every hour for 16 hours. Thedissolution profiles were obtained by plotting the cumulative percent ofAPI dissolved against sampling time points. Sink conditions weremaintained throughout all the experiments.

On several trials, USP-3 method was used to conduct the dissolutionstudies. These dissolution tests were performed for 16 hours total withthe following breakdown: 2 hours using 900 mL of Simulated Gastric Fluid(SGF) at pH 1.2 with 0.5% of Sodium Lauryl Sulfate (SLS), followed by 2hours in 900 mL of Acetate Buffer at a pH of 4.5, followed by 12 hoursin 900 mL of Phosphate Buffer Simulated Intestinal Fluid (SIF) at a pHof 6.8. These results were plotted with the in-vivo data and theBupropion HCI data in order for a comparison to be made.

Study on Batch BUP-HBr-XL-009-5

The formulation was granulated using NIRO Fluid Bed. After granulationwas completed, the batch was screened and then prior to compression thelubricant (COMPRITOL® 888) was added. The final blend was compressedinto 348 mg tablets using the Beta press with 9 mm and 10 mm standard,round, concave tooling. Table 10 describes the amounts of each materialin the granulation of the 348 mg tablets. A first compression run wasdone to produce tablets with different hardness values so as todetermine the effects of hardness, if any, on the dissolution (FIG. 5).Dissolution was conducted on the 348 mg cores in order to determinetheir release (FIG. 6).

The granulation results show that the average granulation time is 2.0hours and the average LOD % is 0.345%. Tables 11 and 12 summarize thetheoretical and actual values of the parameters that were monitored inthe compression process using the 9 mm and 10 mm tooling, respectively.

In order to determine the tablet hardness for this study, tablets ofdifferent hardness values were compressed and dissolution was conductedon them to see the difference.

Tablets with a hardness of 4 kp, 6-7 kp and 9-10 kp were compressed andthe dissolution profiles of each were shown in FIG. 5. It was observedthat there was no significant difference between the three differenthardness ranges.

The dissolution profiles of the 348 mg (FIG. 6) and 174 mg cores (FIG.7) showed that the cores were releasing approximately 100 percent of APIin an hour.

Dissolution of the 10 mm, 348 mg cores was done also in order to see ifthese tablets released faster when compared to the 9 mm cores due totheir larger surface area (FIG. 7).

When the dissolution results of the 9 mm and 10 mm cores were compared(FIG. 8), the 10 mm cores showed no difference from the 9 mm cores.Thus, the 10 mm cores were no longer manufactured or used in this study.

Study on Batch BUP-HBr-XL-021-5

The Formulation was granulated using NIRO Fluid Bed. The final blend wascompressed into 174 mg tablets using the Beta press with 7 mm standard,round, concave, stainless steel tooling. Table 13 describes the amountsof each material in the granulation of the 174 mg tablets. It was notedthat the 348 and the 174 mg tablets had the same composition and amountsof each material; the only variation was the tablet weight, which wasadjusted at the compression stage. Dissolution was conducted on the 174mg cores in order to see their release (FIG. 9).

The granulation results show that the granulation time is 2 hours 6minutes and the average LOD % is 0.26%. Table 14 summarizes thetheoretical and actual values of the parameters that were monitored inthe compression process using the 7 mm tooling.

The dissolution profile of the 174 mg (FIG. 9) showed that the coreswere releasing approximately 100 percent of API in an hour.

Study on Batch BUP-HBr-XL-348 mg-013-5

Using 348 mg tablets, an ethylcellulose (e.g. ETHOCEL® or “EC”) coatingfollowed by a Final coating, were sprayed onto the tablets using theO′Hara Labcoat II Coating Equipment. The materials used in theethylcellulose coating, their percent contribution to the totalsolution, the amounts of each in the batch and the percentage of thesolids in the solution were all listed in Table 15.

The parameters are as follows: Spray Rate: 13 g/min; Pan Speed: 12.0rpm; Inlet Air: 50° C.; Product Temperature: 35° C. ±5° C.; and SupplyAir Flow: 200 CFW.

It took 2 hours and 25 minutes to coat the tablets with a weight gain of32 mg. Tablet weights were taken and recorded in Table 16 at 28 mg, 30mg, 32 mg, and 34 mg weight gains. The dissolution profile (FIG. 10)shows that the tablets with the 34 mg weight gain of ethylcellulosecoating released Bupropion HBr the slowest when compared to the othersand that the tablets with the 28 mg weight gain released Bupropion HBrthe fastest when compared to the other weight gains.

The materials used in the final coating, their percent contribution tothe total solution, the amounts of each in the batch, the amount ofsolid contribution in grams and the percentage of the solids in thesolution were all listed in Table 17.

The parameters are as follows: Spray Rate: 6 g/min; Pan Speed: 12.0 rpm;Inlet Air: 40° C.; Product Temperature: 35° C. ±5° C.; and Supply AirFlow: 200 CFW.

After this trial run, Chroma-Tone was no longer used due to theformulation problems it caused. First, it limited the composition of theformulation due to its inflexibility, as SYLOID®, PEG and TriethylCitrate ratios could not be varied. Second, the solution foamed andcoagulated, which in turn caused the process for making the coatingsolution to be changed from the original so that it did notre-coagulate. Chroma-Tone can, however, still be considered an optionfor the formulation but different grades and mixtures would need to beused and made in order to accommodate the Bupropion HBr XL tablets.

It took 31 minutes to add a 7 mg weight gain of the final coatingsolution to the tablets. Tablet weights were taken and recorded in Table18 at 4 mg, 5 mg, 6 mg and 7 mg weight gains.

The dissolution profile (FIG. 11) shows that the tablets with the 7 mgweight gain of Final coating released the slowest when compared to theother two weight gains (5 mg and 6 mg weight gains).

Study on Batch BUP-HBr-XL-348 mg-018-5

Using 348 mg tablets, an ethylcellulose coating followed by a finalcoating, were sprayed onto the tablets using the O′Hara Labcoat IICoating Equipment.

The materials used in the ethylcellulose (e.g. ETHOCEL®) coating, theirpercent contribution to the total solution, the amounts of each in thebatch and the percentage of the solids in the solution were all listedin Table 19.

The parameters are as follows: Spray Rate: 13 g/min; Pan Speed: 12.0rpm; Inlet Air: 50° C.; Product Temperature: 35° C. ±5° C.; and SupplyAir Flow: 200 CFW.

The coating process of this trial took 2 hours and 13 minutes to obtaina 32 mg weight gain. Tablet weights were taken and recorded in Table 20at 26 mg, 28 mg, 30 mg, and 32 mg weight gains.

FIG. 12 shows that the tablets with the 30 mg and 32 mg weight gain ofethylcellulose coating solution released at almost the same rate. Thetablets with the 32 mg weight gain released slower than the tablets withthe 30 mg weight gain in the first 5 hours of dissolution. After 6hours, the tablets with the 32 mg weight gain released slightly fasterthan those with a 30 mg weight gain. The f2 similarity factor confirmedthat the release rate of both weight gains was similar (91.32%).

The materials used in the final coating, their percent contribution tothe total solution, the amounts of each in the batch, the amount ofsolid contribution in grams and the percentage of the solids in thesolution were all listed in Table 21.

The parameters are as follows: Spray Rate: 6 g/min; Pan Speed: 12.0 rpm;Inlet Air: 40° C.; Product Temperature: 35° C. ±5° C.; and Supply AirFlow: 200 CFW.

It took 41 minutes to add a 7 mg weight gain of the final coatingsolution to the tablets. Tablet weights were taken and recorded in Table22 at 4 mg, 5 mg, 6 mg, and 7 mg weight gains.

FIG. 13 shows the release profile of the tablets with the 7 mg weightgain of Final coating.

Study on Batch BUP-HBr-XL-174 mg-022-5

Using 174 mg tablets, an ethylcellulose coating followed by a finalcoating, were sprayed onto the tablets using the O′Hara Labcoat IICoating Equipment.

The materials used in the ethylcellulose (e.g. ETHOCEL®) coating, theirpercent contribution to the total solution, the amounts of each in thebatch and the percentage of the solids in the solution were all listedin Table 23.

The parameters are as follows: Spray Rate: 13 g/min; Pan Speed: 12.0rpm; Inlet Air: 50° C.; Product Temperature: 35° C. ±5° C.; and SupplyAir Flow: 200 CFW.

It took 4 hours and 30 minutes to add a 30 mg weight gain of theethylcellulose coating solution to the tablets. Tablet weights weretaken at 20 mg, 22 mg, 24 mg, 26 mg, 28 mg, 29 mg, and 30 mg weightgains and were recorded in Table 24.

FIG. 14 shows the % dissolved of each of the samples with differentweight gains of ethylcellulose coating (22 mg, 24 mg, 28 mg and 30 mgweight gains). From the graph, it was evident that the tablets with the30 mg weight gain of ethylcellulose coating released slower than theother weight gains. When the release rates of the tablets with the 30 mgand the 28 mg weight gains were compared, there was only a slightdifference noticed in the release. The f2 similarity factor confirmedthe similarity of the two releases (92.34%).

The materials used in the final coating, their percent contribution tothe total solution, the amounts of each in the batch, the amount ofsolid contribution in grams and the percentage of the solids in thesolution were all listed in Table 25.

The parameters are as follows: Spray Rate: 6 g/min; Pan Speed: 12.0 rpm;Inlet Air: 40° C.; Product Temperature: 35° C. ±5° C.; and Supply AirFlow: 200 CFW.

It took 1 hour and 26 minutes to add a 7 mg weight gain of the finalcoating solution to the tablets. Tablet weights were taken and recordedin Table 26 at 4 mg, 5 mg, 6 mg, and 7 mg weight gains.

The dissolution profile (FIG. 15) shows that the tablets with the 7 mgweight gain of final coating released the slowest, in comparison to the5 mg and the 6 mg weight gains.

Study on Batch BUP-HBr-XL-348 mg-023-5

Using 348 mg tablets, an ethylcellulose coating was sprayed onto thetablets using the O′Hara Labcoat II Coating Equipment.

The materials used in the ethylcellulose (e.g. ETHOCEL®) coating, theirpercent contribution to the total solution, the amounts of each in thebatch and the percentage of the solids in the solution were all listedin Table 27.

The parameters are as follows: Spray Rate: 13 g/min; Pan Speed: 12.0rpm; Inlet Air: 50° C.; Product Temperature: 35° C. ±5° C.; and SupplyAir Flow: 200 CFW.

It took 2 hours and 16 minutes to add a 32 mg weight gain of theethylcellulose coating solution to the tablets. Tablet weights weretaken at 26 mg, 28 mg, 30 mg, and 32 mg weight gains and were recordedin Table 28.

The dissolution profile (FIG. 16) shows that the tablets with the 32 mgweight gain of ethylcellulose coating, when compared to the tablets withthe 26 mg, 28 mg and the 30 mg weight gain of ethylcellulose coating,released at the slowest rate.

Study on Batch BUP-HBr-XL-348 mg-025-5

Using 348 mg tablets, an ethylcellulose coating followed by a finalcoating, were sprayed onto the tablets using the O′Hara Labcoat IICoating Equipment.

The materials used in the ethylcellulose (e.g. ETHOCEL® or EC) coating,their percent contribution to the total solution, the amounts of each inthe batch and the percentage of the solids in the solution were alllisted in Table 29.

The parameters are as follows: Spray Rate: 13 g/min; Pan Speed: 12.0rpm; Inlet Air: 50° C.; Product Temperature: 35° C. ±5° C.; and SupplyAir Flow: 200 CFW.

It took 2 hours and 13 minutes to add a 32 mg weight gain of theethylcellulose coating solution to the tablets. Tablet weights weretaken at 26 mg, 28 mg, 30 mg, and 32 mg weight gains and were recordedin Table 30.

The dissolution profile (FIG. 17) shows that the tablets with the 32 mgweight gain of ethylcellulose coating when compared to those with 26 mgweight gain released slower in the beginning and then faster after 7hours. When comparing the tablets with 32 mg weight gain ofethylcellulose coating to those with 30 mg weight gain of ethylcellulosecoating, the tablets with the 32 mg weight gain released slower up until10 hours. The f2 similarity factor showed that the release of thetablets with the 30 mg and 32 mg weight gains were in fact similar(93.72%).

The materials used in the final coating, their percent contribution tothe total solution, the amounts of each in the batch, the amount ofsolid contribution in grams and the percentage of the solids in thesolution were all listed in Table 31.

The parameters are as follows: Spray Rate: 6 g/min; Pan Speed: 12.0 rpm;Inlet Air: 40° C.; Product Temperature: 35° C. ±5° C.; and Supply AirFlow: 200 CFW.

The coating solution was altered for this batch by changing thepercentage of solid from each of the solid components in the solution.The percentage of EUDRAGIT® solid contribution was decreased from 65% to56.5%. The percentage of SYLOID®, CARBOWAX® and Triethyl Citrate wereincreased from 25%, 6.65% and 3.39% to 30%, 9% and 4.5%, respectively.

It took 40 minutes to add a 7 mg weight gain of the final coatingsolution to the tablets. Tablet weights were taken and recorded (Table32) at 4 mg, 5 mg, 6 mg, and 7 mg weight gains. The dissolution profile(FIG. 18) shows that the tablets with the 7 mg weight gains released theslowest of the three samples tested. However, f2 calculation showed thatthe tablets with the 6 mg weight gain released similarly to those withthe 7 mg weight gain of Final coating (93.33%).

Study on Batch BUP-HBr-XL-348 mg-026-5

Using 348 mg tablets, an ethylcellulose coating was sprayed onto thetablets using the O′Hara Labcoat II Coating Equipment.

The materials used in the ethylcellulose (e.g. ETHOCEL® or EC) coating,their percent contribution to the total solution, the amounts of each inthe batch and the percentage of the solids in the solution were alllisted in Table 33.

The parameters are as follows: Spray Rate: 13 g/min; Pan Speed: 12.0rpm; Inlet Air: 50° C.; Product Temperature: 35° C. ±5° C.; and SupplyAir Flow: 200 CFW.

It took 2 hours and 11 minutes to add a 32 mg weight gain of theethylcellulose coating solution to the tablets. Tablet weights weretaken at 26 mg, 28 mg, 30 mg, and 32 mg weight gains and were recordedin Table 34.

The dissolution profile (FIG. 19) shows that the tablets with the 32 mgweight gain of ethylcellulose coating released the slowest when comparedto the other three samples with lower weight gains of ethylcellulosecoating (26 mg, 28 mg and 30 mg).

Study on Batch BUP-HBr-XL-174 mg-027-5

Using 174 mg tablets, an ethylcellulose coating followed by a finalcoating, were sprayed onto the tablets using the O′Hara Labcoat IICoating Equipment.

The materials used in the ethylcellulose (e.g. ETHOCEL® or EC) coating,their percent contribution to the total solution, the amounts of each inthe batch and the percentage of the solids in the solution were alllisted in Table 35.

The parameters are as follows: Spray Rate: 13 g/min; Pan Speed: 12.0rpm; Inlet Air: 50° C.; Product Temperature: 35° C. ±5° C.; and SupplyAir Flow: 200 CFW.

It took 3 hours and 29 minutes to add a 32 mg weight gain of theethylcellulose coating solution to the tablets. Tablet weights weretaken at 22 mg, 24 mg, and 26 mg weight gains and were recorded in Table36.

The dissolution profile (FIG. 20) shows that the tablets with the 26 mgweight gain of ethylcellulose coating released the slowest of the threesamples tested.

The materials used in the final coating, their percent contribution tothe total solution, the amounts in each in the batch, the amount ofsolid contribution in grams and the percentage of the solids in thesolution were all listed in Table 37.

The parameters are as follows: Spray Rate: 6 g/min; Pan Speed: 12.0 rpm;Inlet Air: 40° C.; Product Temperature: 35° C. ±5° C.; and Supply AirFlow: 200 CFW.

It took 1 hour and 17 minutes to add a 7 mg weight gain of the finalcoating solution to the tablets. Tablet weights were taken and recordedin Table 38 at 4 mg, 5 mg, 6 mg, and 7 mg weight gains.

The dissolution profile (FIG. 21) shows that the tablets with the 7 mgweight gain of final coating initially released slower that the tabletswith 4 mg, 5 mg and 6 mg weight gains. However, at approximately 12hours, all 4 samples were releasing similarly.

Example 3 Preparation and Stability Study of Bupropion Hbr Polymorphs I,II and III Bupropion Hydrobromide Polymorphic Forms I, II and III werePrepared in the Following Manner and Their Stability was Studied Underthe Conditions Described Below Form I:

A 250 ml flask equipped with overhead stirrer and gas inlet was chargedwith 34 g of bupropion base and 138 ml of isopropanol. The solution wasmaintained under stirring while 13g of gaseous HBr was introducedthrough the gas inlet in a time of 20′ while the internal temperature ofthe mixture raises from 25° C. to 40° C. During the gas addition a heavywhite precipitate formed. At the end of the gas addition the temperatureof the mixture was raised to reflux (80° C.), to get complete solutionof the suspended solid. The temperature was then lowered to 25° C. in 1hour and further lowered to 0-5° C. in 1 additional hour. Theprecipitate obtained was filtered and washed with 20 ml of coldisopropanol. The discharged wet solid was dried under vacuum (30 mmHg)in a static drier at 50° C. for 16 hours. 34 g of bupropion hydrobromideform I were obtained.

Samples of bupropion hydrobromide form I were subjected to theconditions for the accelerated stability study and the shelf lifestability study as described for example in U.S. Pat. No. 7,241,805 (eg.see examples 10 and 11), the contents of which are incorporated hereinby reference. PXRD studies carried out after 3 months and 6 months foreach sample gave the same results. The PXRD profile of one of thesamples of form I after 6 months in the accelerated stability conditionis provided in FIG. 24.

Form II:

10 g of bupropion hydrobromide form I were dissolved in a mixture of 170ml of acetone and 7 ml of water. The mixture was brought to reflux withdissolution of the solid. The solution was then cooled to roomtemperature. After one night the precipitate formed was filtered anddried at 40° C. under vacuum (30 mmHg) for 12 hours. 2.4 g of bupropionhydrobromide form II were obtained. A sample of the product was preparedfor an accelerated stability test, in ICH (International Conference onHarmonisation of Technical Requirements for Registration ofPharmaceuticals for Human Use) conditions (40° C./75% R.H.), by sealingthe product in polyethylene bags, which in turn were placed in aluminiumbags containing silica and sealed and placed in the stability chamber inICH conditions (40° C./75% R.H.). The crystalline form was checked aftermaintaining the product under these conditions for 1 month. The PXRDprofile shown in FIG. 27 shows that the compound is still in form II.This demonstrates the stability of crystal form II under theseconditions.

Form III:

20 g of bupropion hydrobromide form 1 and 96 ml of absolute ethanol wereplaced in a 250 ml flask. The mixture was brought to reflux obtainingcomplete dissolution of the solid. The solution was then cooled to roomtemperature without stirring and left in these conditions for 18 hours.The resulting crystalline solid was then filtered and dried under vacuum(30 mmHg) at 50° C. for 4 hours. 11.2 g of bupropion hydrobromide formIII were obtained. A sample of the product was prepared for stabilitytesting by sealing the product in polyethylene bags, which in turn wereplaced in aluminium bags containing silica and sealed, and placed in thestability chamber in ICH conditions (40° C./75% R.H.). The crystallineform was checked after maintaining the product in these conditions for 1month. The PXRD profile shown in FIG. 30 demonstrates that the productis not stable in this form under these conditions, as the majority ofthe product changed to form II.

Example 4 Preparation of Bupropion Hbr Polymorphs Iv, V, VI and VII, andAmorphous Bupropion HBr

Bupropion hydrobromide polymorphic forms IV, V, VI and VII and amorphousform were prepared in the following manner:

Form IV:

50 mg of bupropion hydrobromide form I is dissolved in 4 ml ofchloroform, with stirring, and filtered on a Whatman filter (0.45micron). The solution obtained is left to evaporate at room temperatureuntil the solvent has evaporated completely. In this way we obtain a wetsolid crystalline residue comprising bupropion hydrobromide in form IV.The PXRD, DSC, TGA and IR profiles of this crystalline form are shownrespectively in FIGS. 31, 32, 33 and 34. The sample is then dried toconstant weight and the PXRD, DSC, TGA and IR analyses are repeated,obtaining profiles identical to those obtained on the sample prior todrying.

Form V:

100 mg of bupropion hydrobromide form I is suspended in 2 ml of1,4-dioxan and stirred at room temperature for seven days. Thesuspension obtained is then filtered on Whatman filter paper anddischarged wet from the filter. In this way we obtain a wet crystallinesolid residue comprising bupropion hydrobromide in form V. The PXRD,DSC, TGA and IR profiles of this crystalline form are shown respectivelyin FIGS. 35, 36, 37 and 38. The sample is then dried to constant weightand the PXRD, DSC, TGA and IR analyses are repeated, obtaining profilesidentical to those obtained on the sample prior to drying.

In another preparation of form V, a mixture of 50 mg of bupropionhydrobromide form 1 and 50 mg of bupropion hydrobromide form II issuspended in 2 ml of 1,4-dioxan and stirred at room temperature forseven days. The suspension obtained is then filtered on Whatman filterpaper and discharged wet from the filter. In this way we obtain a wetcrystalline solid residue comprising bupropion hydrobromide in form V.The PXRD, DSC, TGA and IR profiles of the wet product and product afterdrying are identical to those shown respectively in FIGS. 35, 36, 37 and38.

Form VI:

2 g of bupropion hydrobromide form I is suspended in 15 ml of 1-propanoland refluxed, observing dissolution of the solid. The solution obtainedis then cooled at a rate of 0.45° C./min to a temperature of 20° C. Thesolid obtained is then filtered, obtaining bupropion hydrobromide formVI. The PXRD, DSC, TGA and IR profiles of this crystalline form areshown respectively in FIGS. 39, 40, 41 and 42. The sample is then driedto constant weight and the PXRD, DSC, TGA and IR analyses are repeated,obtaining profiles identical to those obtained on the sample prior todrying.

Form VII:

50 mg of bupropion hydrobromide form I is dissolved in 4 ml ofdimethylformamide (DMF), with stirring, and is filtered on a Whatmanfilter (0.45 micron). The solution obtained is left to evaporate at 60°C. until the solvent has evaporated completely. As a result, we obtain awet solid crystalline residue comprising bupropion hydrobromide in formVII. The PXRD, DSC, TGA and IR profiles of this crystalline form areshown in FIGS. 43, 44, 45 and 46 respectively. The sample is then driedto constant weight and the PXRD, DSC, TGA and IR analyses are repeated,obtaining profiles identical to those obtained on the sample beforedrying.

Amorphous Form:

5 g of bupropion hydrobromide form I is dissolved at room temperature in195 ml of deionized water. The solution is loaded in a 1-liter flask andfrozen by immersion of the flask in rotation in a rotary evaporator, ona bath of isopropanol and dry ice maintained at a temperature of −50° C.The freezing process is continued for two hours, then the flask ismounted in lyophilization apparatus and submitted to lyophilization inthe following conditions:

Apparatus: CHRIST Alpha 1-4 LSC

Coil conditioning temperature: −30° C.Pump conditioning pressure: atmospheric.Condenser temperature during drying: −50° C.Residual pressure during drying: 0.02 mbarDrying time: 18 hours.

At the end of the process, a solid is discharged from the flask and isanalyzed by X-ray diffraction. The profile obtained is shown in FIG. 47;it is the typical PXRD profile of an amorphous solid.

In another preparation of bupropion hydrobromide in amorphous form, asample of bupropion hydrobromide form I is dissolved in 4 ml ofp-xylene, with stirring. After about one hour in these conditions, thesolution is filtered on Whatman paper (0.45 micron) and the solutionobtained is left to evaporate until the solvent has been removed. Theresultant solid is analyzed by PXRD, giving the profile shown in FIG.48. It can be seen from the PXRD profile that the product is obtained inamorphous form.

Example 5 Polymorph Screening Solvent Screening:

We analyzed the powder sample obtained by recrystallization fromdifferent solvents chosen on the basis of the following parameters: (i)dielectric constants; (ii) boiling point (BP); (iii) melting point (MP);and (iv) solubility of sample. See Table 40 for solvents used during theexperiments.

Qualitative Solubility Screening:

Bupropion hydrobromide (50 mg) was introduced in 4 mL of solvent understirring for about 1 hour at room temperature. See Table 41 for thequalitative solubility data.

Room Temperature Recrystallization:

Bupropion hydrobromide (50 mg) was dissolved in 4 mL of solvent understirring, after about 1 hour the solution was filtered with a Whatmanfilter (0.45 μm) and left to evaporate at room temperature (RT). Thesolutions were evaporated at RT for 3 days, in some cases for 1 week.Four different crystal forms were identified: Form I, Form IV, Form VIIand an amorphous phase. See Table 42 for the recrystallization results(experiments of evaporation of Bupropion Hydrobromide at roomtemperature).

Low Temperature Recrystallization:

Bupropion hydrobromide (50 mg) was dissolved in 4 mL of solvent understirring, after about 1 hour the solution was filtered with a Whatmanfilter (0.45 μm) and left to evaporate at 4° C. for 1-2 weeks. See Table43 for the recrystallization results (experiments of evaporation ofbupropion hydrobromide at low temperature).

High Temperature Recrystallization:

Bupropion hydrobromide (50 mg) was dissolved in 4 mL of solvent understirring, after about 1 hour the solution was filtered with a Whatmanfilter (0.45 μm) and left to evaporate at 60° C. for 2-3 days. See Table44 for the recrystallization results (experiments of evaporation ofbupropion hydrobromide at high temperature).

Low Pressure Recrystallization:

Bupropion hydrobromide (50 mg) was dissolved in 4 mL of solvent understirring, after about 1 hour the solution was filtered with a Whatmanfilter (0.45 μm) and left to evaporate at low pressure for 1-2 days. SeeTable 45 for the recrystallization results (experiments of evaporationof bupropion hydrobromide at low pressure).

Example 6 Slurries

Slurries of Form 1-7 days

Slurry experiments of Form I were performed at room temperature toverify if Form I is the thermodynamic crystal form. 0.050 g of Form Iwas suspended in 2 ml of solvent and stirred for 1 week. The sample wasfiltered and analyzed by X-ray diffraction. In the large majority of theexperiments, Form I converts into Form II. As such, Form II is thethermodynamic stable form of bupropion hydrobromide. By 1,4-Dioxane, anew crystal form was obtained named Form V. See Table 46 for the Form Islurries results (7 days).

Further slurry experiments of Form I were performed at room temperatureusing 0.5 g of powder in 10 mL of solvent to confirm the resultsobtained even in large scale. With both Ethyl Acetate and p-Xylene assolvents, Form I was found to convert into Form II.

Slurries of Form I ±30 Days

0.050 g of Form I were suspended in 2 ml of solvent and stirred at roomtemperature for 4 weeks (30 days). The sample was filtered and analyzedby X-ray diffraction. By 1,4-Dioxane, Form V was obtained. Bytetrahydrofuran, Form II and Form VII were obtained. In all otherexperiments, Form I converts to Form II; showing that Form II is thethermodynamic stable form of bupropion hydrobromide. See Table 47 forthe Form I slurries results (30 days).

Slurries of Form I Mixed with Form II-7 Days

Slurry experiments of mixtures of Form I and Form II were performed atroom temperature to verify their thermodynamic stability. 0.040 g ofForm I+0.040 g of Form II were suspended in 4 ml of solvent and stirredfor 1 week (7 days). The samples were filtered and analyzed by X-raydiffraction. By 1,4-Dioxane, Form V was obtained. In all otherexperiments, Form I converts to Form II; showing that Form II is thethermodynamic stable form of bupropion hydrobromide. See Table 48 forthe Form I+Form II slurries results (7 days).

Slurries of Form II Mixed with Form III-7 Days

Slurry experiments of mixtures of Form II and Form III were performed atroom temperature to verify their thermodynamic stability. 0.040 g ofForm II +0.040 g of Form III were suspended in 4 ml of solvent andstirred for 1 week (7 days). The samples were filtered and analyzed byX-ray diffraction. By 1,4-Dioxane, Form V was obtained. In all otherexperiments, Form III converts to Form II; showing that Form II is thethermodynamic stable form of bupropion hydrobromide. See Table 49 forthe Form II +Form III slurries results (7 days).

Slurries of Form II Mixed with Form IV-7 Days

Slurry experiments of mixtures of Form II and Form IV were performed atroom temperature to verify their thermodynamic stability. 0.040 g ofForm II +0.040 g of Form IV were suspended in 4 ml of solvent andstirred for 1 week (7 days). The samples were filtered and analyzed byX-ray diffraction. By 1,4-Dioxane, Form V was obtained. In all otherexperiments, Form IV converts to Form II; showing that Form II is thethermodynamic stable form of bupropion hydrobromide. See Table 50 forthe Form II+Form IV slurries results (7 days).

Slurries of Form II Mixed with Form V-7 Days

Slurry experiments of mixtures of Form II and Form V were performed atroom temperature to verify their thermodynamic stability. 0.040 g ofForm II +0.040 g of Form V were suspended in 4 ml of solvent and stirredfor 1 week (7 days). The samples were filtered and analyzed by X-raydiffraction. By 1,4-Dioxane, Form V was obtained. In all otherexperiments, Form V converts to Form II; showing that Form II is thethermodynamic stable form of bupropion hydrobromide. See Table 51 forthe Form II +Form V slurries results (7 days).

Slurries of Form H Mixed with Form VI-7 Days

Slurry experiments of mixtures of Form II and Form VI were performed atroom temperature to verify their thermodynamic stability. 0.040 g ofForm II +0.040 g of Form VI were suspended in 4 ml of solvent andstirred for 1 week (7 days). The samples were filtered and analyzed byX-ray diffraction. By 1,4-Dioxane, Form V was obtained. In all otherexperiments, Form VI converts to Form II; showing that Form II is thethermodynamic stable form of bupropion hydrobromide. See Table 52 forthe Form II +Form VI slurries results (7 days).

Slurries of Form II Mixed with Form VII-7 Days

Slurry experiments of mixtures of Form II and Form VII were performed atroom temperature to verify their thermodynamic stability. 0.040 g ofForm II +0.040 g of Form VII were suspended in 4 ml of solvent andstirred for 1 week (7 days). The samples were filtered and analyzed byX-ray diffraction. By 1,4-Dioxane, Form V was obtained. In all otherexperiments, Form VII converts to Form II; showing that Form II is thethermodynamic stable form of bupropion hydrobromide. See Table 53 forthe Form II +Form VII slurries results (7 days).

Example 7 Slurries in 2-Propanol

Slurries of Form I at Room Temperature.

0.050 g of Form I were suspended in 4 ml of solvent and stirred at roomtemperature. for 1 week (7 days). The sample was filtered and analyzedby X-ray diffraction. By 2-propanol, Form I converted to Form II at roomtemperature.

Slurries of Mixture Form I and Form II at Room Temperature.

0.040 g of Form I+0.040 g of Form II were suspended in 4 ml of solventand stirred at room temperature for 1 week (7 days). The sample wasfiltered and analyzed by X-ray diffraction experiments. By 2-propanol,Form I converted to Form II at room temperature. The final result wasthat Form II was obtained.

Slurries of Form II at Room Temperature.

0.050 g of Form II were suspended in 4 ml of solvent and stirred at roomtemperature for 1 week (7 days). The sample was filtered and analyzed byX-ray diffraction experiments. The final result was that by 2-propanol,Form II was obtained.

Slurries of Form I at 50° C.

0.050 g of Form I were suspended in 4 ml of solvent and stirred at 50°C. for 1 Week (7 days). The sample was filtered and analyzed by X-raydiffraction experiments. By 2-propanol, Form I converted to Form II at50° C.

Slurries of Mixture Form I and Form II at 50° C.

0.040 g of Form I+0.040 g of Form II were suspended in 4 ml of solventand stirred at 50° C. for 1 week (7 days). The sample was filtered andanalyzed by X-ray diffraction experiments. By 2-propanol, Form Iconverted to Form II at 50° C. The final result was that Form II wasobtained.

Slurries of Mixture Form I and Form II at 80° C.

Form I+Form II were suspended in solvent and stirred at 80° C. for 14hours. The sample was filtered and analyzed by X-ray diffractionexperiments. By 2-propanol, Form I remained as Form I, whereas Form IIconverted to Form I after this assay at 80° C. Slurry in 2-propanol at80° C. is an atypical experiment because if we consider the boilingpoint of the solvent, it could be defined as a combination between aslurry and precipitation experiment. Form I was obtained during theprecipitation from supersaturated solution by 2-propanol. However thehigh temperature and the reflux produce the energetic conditions neededby the stable crystal form (Form II) to convert to the metastablecrystal form (Form I).

Example 8 Precipitation Precipitation by Anti-solvent Addition

Bupropion hydrobromide was dissolved at room temperature in the solventin which the sample showed high solubility, ethyl acetate was chosen asantisolvent. The samples were filtered and analyzed by X-raydiffraction. Form I converts into Form II using chloroform, and alsowith benzyl alcohol. The other experiments yield only Form I. See Table54 for Form I precipitation results by anti-solvent addition.

Precipitation from Oversaturated Solution

Bupropion hydrobromide Form I was dissolved at 100° C. in solvent toobtain the oversaturated solution. The cooling rate applied was 0.45°C./min. The samples were filtered and analyzed by X-ray diffraction.Form I converts into Form VI using 1-Propanol, and into Form V using1,4-Dioxane. The other experiments yield only Form I. See Table 55 forForm I precipitation results by oversaturated solution.

Precipitation from 2-Propanol

Bupropion hydrobromide Form I was dissolved in 2-propanol at 100° C. toobtain oversaturated solution. The cooling rate applied was 0.45°C./min. The experiment was repeated to verify the reproducibility of thecrystal form obtained. The samples were filtered and analyzed by X-raydiffraction. The precipitation experiments yielded only Form I.

Example 9 Stability Tests on Bupropion Hydrobromide Polymorphs

Stability tests were performed on bupropion hydrobromide Form I, FormII, Form III, Form IV, Form V and Form VI. The powders were stored in acontrolled atmosphere (85% R.H.) at 40° C. Form I and Form II werestored for 7 and 30 days respectively, while the other forms were storedonly for 30 days. The sample was positioned on the sample-holder whichwas introduced, without any cover, into the humidity chamber at 40° C.The layer of the sample on the sample-holder was about 0.5 cm. Theexperiments after 7 and 30 days evidenced that Form I and II did notshow modification in their XRD pattern, and remained as Form I and FormII respectively. Form III, Form IV and Form V converted into Form Iafter 30 days, while Form VI converted into a mixture of Form I+Form IIafter 30 days.

In addition, stability tests were performed on bupropion hydrobromideForm VII. Form VII was stored for 28 days at 25° C., 75% R.H. The XRDpattern did not show modification, and as such, Form VII was evidencedto be stable after 28 days.

Example 10 Characterization

PXRD, DSC, TGA and IR analyses were obtained for Bupropion HydrobromidePolymorph Form I, Form II, Form III, Form IV, Form V, Form VI, and FormVII. PXRD analyses were obtained for the amorphous form. With respect tothe PXRD analyses, the Peak List is shown for Form I, Form II, Form III,Form IV, Form V, Form VI, Form VII and the amorphous form in Table 56,Table 57, Table 58, Table 59, Table 60, Table 61, Table 62 and Table 63respectively. Table 64 shows the TGA and DSC summary for Form I, FormII, Form III, Form IV, Form V, Form VI, and Form VII.

TABLE 1 Each trial's contents and amounts of each material per partAmount (g) Materials Part 1 Part 2 Part 3 Part 4 Part 5 Bupropion HBr2062.5 2062.5 2062.5 2062.5 2062.5 PVA 68.75 68.75 68.75 68.75 68.75Purified Water 1452.5 1452.5 1452.5 1452.5 1452.5

TABLE 2 Summary of specifications for granulation procedure.Specification Range Target Fan Speed Slow Slow Air Volume (CMH) 60-65 65Exhaust Temperature (° C.) 35-45 40 Supply Temperature (° C.) 60-65 65Product Temperature (° C.) 35-55 45 Atomizing Air Pressure (Bar/psi) 3535 Pump Speed (rpm) 18 18 Liquid Flow Rate (g/min) 13 13 Bed Dew Point(MMWC)  0 0 Filter Dew Point (MMWC 100-300 200

TABLE 3 The amount of lubricant in the final formulation was 343.75 g,which was 3.125% of the total. Materials Amount (g) Part 1 2131.25 Part2 2131.25 Part 3 2131.25 Part 4 2131.25 Part 5 2131.25 COMPRITOL ® 888343.75 Total 11000.0

TABLE 4 Summary of Specifications for Tablet Press Set-up. ParametersSettings/Ranges Pre-Compression Thickness (mm) 2 Control Thickness (mm)1.5 Fill Thickness (mm) 7-8 Overload Pressure (Tons) 1.5-2.0 Tablets perminute 450-500 Feeder Speed 1-2 Feeder Control Auto

TABLE 5 Summary of specifications for compression Specification forSpecification for Parameters 174 mg Tablet 348 mg Tablet IndividualTablet Weight 185.6 ± 5% 371.2 ± 5% (mg) (176.3 mg-194.9 mg) (352.6mg-389.8 mg) Average Tablet Weight 185.6 ± 3% 371.2 ± 3% (mg) (180.0mg-191.2 mg) (360.1 mg-382.3 mg) Tablet Hardness (SC) 6.0-12.0 6.0-12.0Tablet Thickness (mm) 5.0-6.0 4.5-5.0 Friability (%) <0.8 <0.8

TABLE 6 Formulations used as the ethylcellulose (e.g. ETHOCEL ® or EC)coating on the 174 mg and 348 mg Bupropion HBr cores. FORMULATION 1FORMULATION 2 FORMULATION 3 ETHOCEL ® (Ethyl ETHOCEL ® (Ethyl ETHOCEL ®(Ethyl Cellulose) Cellulose) Cellulose) Standard 100 Premium Standard100 Premium Standard 100 Premium Povidone USP Povidone USP Povidone USP(KOLLIDON ® 90F) (KOLLIDON ® 90F) (KOLLIDON ® 90F) Polyethylene GlycolPolyethylene Glycol Polyethylene Glycol 4000 4000 4000 Ethyl Alcohol 95%Dibutyl Sebacate Ethyl Alcohol 95% USP Ethyl Alcohol 95% USP USPIsopropyl Alcohol (IPA)

TABLE 7 Formulations used as the Final Coats on the 174 mg and 348 mgBupropion HBr tablets. FORMULATION A FORMULATION B EUDRAGIT ® L30D-55EUDRAGIT ® L30D-55 Chroma-Tone DEB 5156-CLE SYLOID ® 244FP PurifiedWater Polyethylene Glycol 4000 Triethyl Citrate Purified Water

TABLE 8 Summary of Specifications that were kept constant in theethylcellulose coating Process. Operational Process Parameters RangesTarget Inlet Temperature for coating (° C.) SV: 40 ± 5 40 PV: 40 ± 5Inlet Temperature for Drying (° C.) 30-35 35 Exhaust Temperature 30 ± 1030 Product Temperature 25-35 28 ΔP Differential Pressure (W.C) (−0.1)-(−0.12) −0.10 Supply Air Flow (CFM) 200 ± 50  200 Pan Speed(rpm) 2.5-12  5.0 Atomizing Air (psi) 35-40 35 Pattern Air (psi) 20-3025 Spray Rate (g/min)  5-15 6.0

TABLE 9 Summary of Specifications that were kept constant in the Finalcoating Process. Operational Process Parameters Ranges Target InletTemperature for coating (° C.) SV: 50 ± 5 50 PV: 50 ± 5 InletTemperature for Drying (° C.) 40 ± 5 40 Exhaust Temperature 35 ± 5 38Product Temperature 35 ± 2 35 ΔP Differential Pressure (W.C) (−0.1)-(−0.12) −0.10 Supply Air Flow (CFM) 200 ± 50  200 Pan Speed(rpm)  2.5-15 12.0 Atomizing Air (psi)  25-35 35 Pattern Air (psi) 20-30 25 Spray Rate (g/min)  5-15 13.0

TABLE 10 Materials used in one part of the batch, the percentage of eachconstituent, the amount per tablet and the amount per batch, forBUP-HBr-XL-009-5 Materials % mg/tablet Batch Quantity (g) Bupropion HBr93.75 348.00 1993.75 PVA 3.125 11.60 68.75 COMPRITOL ® 888 3.125 11.6068.75 Total 100.00 371.2 mg 2131.25

TABLE 11 Results obtained using 9 mm tooling for batch BUP-HBr-XL-009-5.Parameters Theoretical Actual Average Individual Tablet Weight 371.2 mg371.5 mg Average Hardness 6.0-12.0 SC 10.77 SC Average Thickness 5.0-6.0mm 5.60 mm Friability <0.8% 0%

TABLE 12 Results obtained using 10 mm tooling for batchBUP-HBr-XL-009-5. Parameters Theoretical Actual Average IndividualTablet Weight 371.2 mg 366.5 mg Average Hardness 6.0-12.0 SC 7.50 SCAverage Thickness 5.0-6.0 mm 4.97 mm Friability <0.8% 0%

TABLE 13 Materials used in one part of the batch, the percentage of eachconstituent, the amount per tablet and the amount per batch for batchBUP-HBr-XL-021-5. Materials % mg/tablet Batch Quantity (g) Bupropion HBr93.75 174.00 1993.75 PVA 3.125 5.80 68.75 COMPRITOL ® 888 3.125 5.8068.75 Total 100.00 185.60 2131.25

TABLE 14 Results obtained using 7 mm tooling for batch BUP-HBr-XL-021-5.Parameters Theoretical Actual Average Individual Tablet Weight 185.6 mg186.8 mg Average Hardness 6.0-12.0 SC 9.23SC Average Thickness 4.5-5.0mm 4.70 mm Friability <0.8% 0%

TABLE 15 Materials used in the ethylcellulose coating and theirquantities for batch BUP-HBr-XL-348-013-5. % Contribution Batch to TotalQuantity % of Solids Materials Solution (g) in Solution ETHOCEL ® (EthylCellulose) 3.60 77.44* 38.74 Standard 100 Premium Povidone USP 4.60099.22* 49.64 (KOLLIDON ® 90F) PEG 4000 1.07 23.23* 11.62 Ethyl Alcohol95% USP 86.44 1859.50 N/A Isopropyl Alcohol 99% USP 4.54 97.87 N/A Total100.00 2151.00 100.00 *Total solid component of the formulation included77.44 g of ethylcellulose (e.g. ETHOCEL ®), 99.22 g of Povidone and23.23 g of PEG 4000, which gave a total solid amount of 199.89 g. Thesolid component of the formulation made up 9% of the total solution andthe remaining 91% was made up of liquid.

TABLE 16 Theoretical and Actual Tablet weights at 28 mg, 30 mg, 32 mgand 34 mg weight gains for batch BUP-HBr-XL-348-013-5. Weight Gain (mg)Theoretical Weight (mg) Actual Weight (mg) 28.0 400.0 401.3 30.0 402.0402.6 32.0 404.0 404.5 34.0 406.0 406.8

TABLE 17 Materials used in the Final coating and their quantities forbatch BUP-HBr-XL-348-013-5. % % of Contribution Batch Amount Solids toTotal Quantity of Solid in Materials Solution (g) (g) SolutionEUDRAGIT ® L30 22.73 104.8 31.44 65.00* D-55 Chroma-Tone DEB 3.66 16.9016.90 35.00** 5156-CLE Purified Water (1) 21.78 100.40 N/A N/A PurifiedWater (2) 51.89 239.20 N/A N/A Total 100.00 460.95 48.34*** 100.00 *Thepercentage of EUDRAGIT ®, solid, that contributed to the total amount ofsolid was 65%. **The percentage of Chroma-Tone, solid, that contributedto the total amount of solid was 35%. ***The Total amount of solid(48.34 g) was 10.5% of the total solution.

TABLE 18 Theoretical and Actual Tablet weights at 4 mg, 5 mg, 6 mg and 7mg weight gains. Weight Gain (mg) Theoretical Weight (mg) Actual Weight(mg) 4.0 410.0 410.5 5.0 411.0 410.8 6.0 412.0 412.4 7.0 413.0 413.9

TABLE 19 Materials used in the ethylcellulose coating and theirquantities for batch BUP-HBr-XL-348 mg-018-5. % Contribution Batch % ofto Total Quantity Solids in Materials Solution (g) Solution* ETHOCEL ®(ethylcellulose) 3.42 73.57 38.00 Standard 100 Premium Povidone USP 4.4194.86 49.00 (KOLLIDON ® 90F) PEG 4000 1.17 25.17 13.00 Ethyl Alcohol 95%USP 86.45 1859.53 N/A Isopropyl Alcohol 99% USP 4.55 97.87 N/A Total100.00 2151.00 100.00 *Total solid included 73.57 g of ethylcellulose94.86 g of Povidone and 25.17 g of PEG 4000. This gave a total of 193.6g total solid amount.

TABLE 20 Theoretical and Actual Tablet weights at 26 mg, 28 mg, 30 mg,and 32 mg weight gains for batch BUP-HBr-XL-348 mg-018-5. TheoreticalWeight Gain (mg) Weight (mg) Actual Weight (mg) 26.0 398.0 397.7 28.0400.0 399.5 30.0 402.0 401.5 32.0 404.0 404.0

TABLE 21 Materials used in the Final coating and their quantities forbatch BUP-HBr-XL-348 mg-018-5. % Contribution Batch Amount of to TotalQuantity Solid % of Solids Materials Solution (g) (g) in SolutionEUDRAGIT ® 22.75 104.86 31.46 65.00* L30D D-55 SYLOID ® 2.62 12.08 12.0825.00** 244FP CARBOWAX ® 0.70 3.22 3.22 6.65** 4000 Triethyl Citrate0.36 1.64 1.64 3.39** Purified Water (1) 33.84 156.00 N/A N/A PurifiedWater (2) 39.73 183.15 N/A N/A Total 100.00 460.95 48.40*** 100.00 *Thepercentage of EUDRAGIT ®, solid, that contributed to the total amount ofsolid was 65%. **The percentage of SYLOID ®, CARBOWAX ® 4000 andTriethyl Citrate that contributed to the total amount of solid was 25%,6.65% and 3.39%, respectively. This gave a total of 35%. ***The totalamount of solid (48.4 g) was 10.5% of the total solution.

TABLE 22 Theoretical and Actual Tablet weights at 4 mg, 5 mg, 6 mg, and7 mg weight gains for batch BUP-HBr-XL-348 mg-018-5. Theoretical WeightGain (mg) Weight (mg) Actual Weight (mg) 4.0 408.0 408.5 5.0 409.0 409.36.0 410.0 410.7 7.0 411.0 411.1

TABLE 23 Materials used in the ethylcellulose coating and theirquantities for batch BUP-HBr-XL-174 mg-022-5. % Contribution Batch % ofSolids to Total Quantity in Materials Solution (g) Solution* ETHOCEL ®(ethylcellulose) 3.60 116.12 40.00 Standard 100 Premium Povidone USP(KOLLIDON ® 4.32 139.34 48.00 90F) PEG 4000 1.08 34.84 12.00 EthylAlcohol 95% USP 86.45 2788.54 N/A Isopropyl Alcohol 99% USP 4.55 146.76N/A Total 100.00 3225.60 100.00 *Total Solid included 116.12 g ofETHOCEL ®, 139.34 g of Povidone and 34.84 g of PEG 4000. This gave atotal solid amount of 290.3 g.

TABLE 24 Theoretical and Actual Tablet weights at 20 mg, 22 mg, 24 mg,26 mg, 28 mg, 29 mg, and 30 mg weight gains for batch BUP-HBr-XL-174mg-022-5. Theoretical Weight Gain (mg) Weight (mg) Actual Weight (mg)20.0 206.0 206.1 22.0 208.0 207.8 24.0 210.0 210.2 26.0 212.0 211.5 28.0214.0 213.7 29.0 215.0 214.9 30.0 216.0 216.5

TABLE 25 Materials used in the Final coating and their quantities forbatch BUP-HBr-XL-174 mg-022-5. % Contribution Batch Amount of % to TotalQuantity Solid of Solids Materials Solution (g) (g) in SolutionEUDRAGIT ® 22.75 104.86 31.46 65.0* L30D D-55 SYLOID ® 244FP 2.62 12.0812.08 25.0** CARBOWAX ® 0.70 3.22 3.22 6.65** 4000 Triethyl Citrate 0.361.64 1.64 3.39** Purified Water (1) 33.84 156.00 N/A N/A Purified Water(2) 39.73 183.15 N/A N/A Total 100.00 460.95 48.40*** 100.00 *Thepercentage of EUDRAGIT ®, solid, that contributed to the total amount ofsolid was 65%. **The percentage of SYLOID ®, CARBOWAX ® 4000 andTriethyl Citrate that contributed to the total amount of solid was 25%,6.65% and 3.39%, respectively. This gave a total of 35%. ***The Totalamount of solid (48.4 g) was 10.5% of the total solution.

TABLE 26 Theoretical and Actual Tablet weights at 4 mg, 5 mg, 6 mg, and7 mg weight gains for batch BUP-HBr-XL-174 mg-022-5. Theoretical WeightGain (mg) Weight (mg) Actual Weight (mg) 4.0 219.0 219.4 5.0 220.0 220.26.0 221.0 221.2 7.0 222.0 223.0

TABLE 27 Materials used in the ethylcellulose coating and theirquantities for batch BUP-HBr-XL-348 mg-023-5. % Contribution Batch % ofto Total Quantity Solids in Materials Solution (g) Solution* ETHOCEL ®(ethylcellulose) 3.69 79.37 42.71 Standard 100 Premium Povidone USP(KOLLIDON ® 3.69 79.37 42.71 90F) PEG 4000 1.26 27.11 14.58 DibutylSebacate, NF 0.36 7.75 N/A Ethyl Alcohol 95% USP 91.00 1957.4 N/A Total100.00 2151.00 100.00 *Total Solid includes 79.37 g of ETHOCEL ®, 79.37g of Povidone, 27.11 g of PEG 4000 and 7.75 g of Dibutyl Sebacate. Thisgave a total solid amount of 193.6 g.

TABLE 28 Theoretical and Actual Tablet weights at 26 mg, 28 mg, 30 mg,and 32 mg weight gains for batch BUP-HBr-XL-348 mg-023-5. TheoreticalWeight Gain (mg) Weight (mg) Actual Weight (mg) 26.0 398.0 399.3 28.0400.0 401.0 30.0 402.0 401.7 32.0 404.0 402.7

TABLE 29 Materials used in the ethylcellulose coating and theirquantities for batch BUP-HBr-XL-348 mg-025-5. % Contribution Batch % ofto Total Quantity Solids in Materials Solution (g) Solution* ETHOCEL ®(ethylcellulose) 3.69 79.40 41.00 Standard 100 Premium Povidone USP(KOLLIDON ® 3.78 81.30 42.00 90F) PEG 4000 1.53 32.90 17.00 EthylAlcohol 95% USP 91.00 1957.40 N/A Total 100.00 2151.00 100.00 *TotalSolid included 79.40 g of ETHOCEL ®, 81.30 g of Povidone and 32.90 g ofPEG 4000. This gave a total solid amount of 193.6 g.

TABLE 30 Theoretical and Actual Tablet weights at 26 mg, 28 mg, 30 mg,and 32 mg weight gains for batch BUP-HBr-XL-348 mg-025-5. TheoreticalWeight Gain (mg) Weight (mg) Actual Weight (mg) 26.0 398.0 397.8 28.0400.0 400.6 30.0 402.0 401.4 32.0 404.0 402.2

TABLE 31 Materials used in the Final coating and their quantities forbatch BUP-HBr-XL-348 mg-025-5. % Contribution Amount of % of to TotalBatch Solid Solids in Materials Solution Quantity (g) (g) SolutionEUDRAGIT ® 19.77 91.13 27.34 56.50* L30D D-55 SYLOID ® 244FP 3.15 14.5214.52 30.00** CARBOWAX ® 0.95 4.36 4.36 9.00** 4000 Triethyl Citrate0.47 2.17 2.17 4.50** Purified Water (1) 21.70 100.00 N/A N/A PurifiedWater (2) 53.96 248.77 N/A N/A Total 100.00 460.95 48.39*** 100.00 *Thepercentage of EUDRAGIT ®, solid, that contributed to the total amount ofsolid was 65%. **The percentage of SYLOID ®, CARBOWAX ® 4000 andTriethyl Citrate that contributed to the total amount of solid was 30%,9% and 4.5%, respectively. This gave a total of 43.5%. ***The Totalamount of solid (48.39 g) was 10.5% of the total solution.

TABLE 32 Theoretical and Actual Tablet weights at 4 mg, 5 mg, 6 mg, and7 mg weight gains for batch BUP-HBr-XL-348 mg-025-5. Theoretical WeightGain (mg) Weight (mg) Actual Weight (mg) 4.0 408.0 408.3 5.0 409.0 408.86.0 410.0 409.5 7.0 411.0 411.1

TABLE 33 Materials used in the ethylcellulose coating and theirquantities for batch BUP-HBr-XL-348 mg-026-5. % Contribution Batch % ofto Total Quantity Solids Materials Solution (g) Solution* ETHOCEL ®(ethylcellulose) 3.69 79.37 41.00 Standard 100 Premium Povidone USP(KOLLIDON ® 3.69 79.37 41.00 90F) PEG 4000 0.36 7.75 4.00 DibutylSebacate, NF 1.26 27.11 14.00 Ethyl Alcohol 95% USP 91.00 1957.4 N/ATotal 100.00 2151.00 100.00 *Total Solid included 79.37 g of ETHOCEL ®,79.37 g of Povidone, 7.75 g of PEG 4000 and 27.11 g of Dibutyl Sebacate.This gave a total solid amount of 193.6 g.

TABLE 34 Theoretical and Actual Tablet weights at 26 mg, 28 mg, 30 mg,and 32 mg weight gains for batch BUP-HBr-XL-348 mg-026-5. Weight Gain(mg) Theoretical Weight (mg) Actual Weight (mg) 26.0 398.0 398.8 28.0400.0 400.5 30.0 402.0 402.5 32.0 404.0 403.6

TABLE 35 Materials used in the ethylcellulose coating and theirquantities for batch BUP-HBr-XL-174 mg-027-5. % Contribution Batch % ofto Total Quantity Solid in Materials Solution (g) Solution* ETHOCEL ®(ethylcellulose) 3.69 138.87 41.00 Standard 100 Premium Povidone USP3.78 142.25 42.00 (KOLLIDON ® 90 F.) PEG 4000 1.53 57.58 17.00 EthylAlcohol 95% USP 91.00 3424.63 N/A Total 100.00 3763.33 100.00 *TotalSolid included 138.87 g of ETHOCEL ®, 142.25 g of Povidone and 57.58 gof PEG 4000. This gave a total solid amount of 338.7 g.

TABLE 36 Theoretical and Actual Tablet weights at 22 mg, 24 mg, and 26mg weight gains for batch BUP-HBr-XL-174 mg-027-5. Weight Gain (mg)Theoretical Weight (mg) Actual Weight (mg) 22.0 208.0 207.7 24.0 210.0210.8 26.0 212.0 212.4

TABLE 37 Materials used in the Final coating and their quantities forbatch BUP-HBr-XL-174 mg-027-5. % Contribution Batch Amount % of to TotalQuantity of Solid Solid in Materials Solution (g) (g) SolutionEUDRAGIT ® L30D 19.77 182.27 54.68 56.5* D-55 SYLOID ® 244FP 3.15 29.0329.03 30.0** CARBOWAX ® 4000 0.95 8.71 8.71 9.0** Triethyl Citrate 0.474.35 4.35 4.5** Purified Water (1) 21.70 200.00 N/A N/A Purified Water(2) 53.98 497.26 N/A N/A Total 100.00 921.62 96.77*** 100.00 *Thepercentage of EUDRAGIT ®, solid, that contributed to the total amount ofsolid was 56.5%. **The percentage of SYLOID ®, CARBOWAX ® 4000 andTriethyl Citrate that contributed to the total amount of solid was30.0%, 9.0% and 4.5%, respectively. This gave a total of 43.5%. ***TheTotal amount of solid (9.77 g) was 10.5% of the total solution.

TABLE 38 Theoretical and Actual Tablet weights at 4 mg, 5 mg, 6 mg, and7 mg weight gains for batch BUP-HBr-XL-174 mg-027-5. Weight Gain (mg)Theoretical Weight (mg) Actual Weight (mg) 4.0 216.0 216.6 5.0 217.0217.6 6.0 218.0 217.8 7.0 219.0 219.8

TABLE 39 Bupropion Hydrobromide Polymorphs Cosolvent Yield K. F. TrialSolvent (voll.) (voll.) (%) Form (%) Notes 085 IPA + HBr gas I 0.07Standard procedure 097 Water 2 / 72 I 0.06 098A Methanol 2.4 / II 0.13098B Acetone 17 water 0.7 24 II 0.16 099 Ethanol abs. 4.8 / 56 III 0.12100 IPA 15.1 / 77 I 0.11 102 AcOi-Pr 20 MeOH 3.6 26 I 0.25 108Acetonitrile 20 / 70 I 0.14 109 Dichloromethane / 25 II 0.21 30 110Water 2 HBr 48% 1 83 I 0.12 111 IPA 6 HBr 48% 1 69 I 0.32 112 MTBE 10MeOH 3 67 I 0.18 113 Toluene 10 MeOH 1.25 40 II 0.39 114 DMC 10 MeOH1.75 67 II 0.17 115 t-BuOH 20 Water 0.55 74 I 0.15 116 Form I inrotavapor I 0.45 100° C. 24 h 117 IPA 10 Water 0.125 88 I 0.32 118Toluene 10 MeOH 1.15 99 I 0.16 119 IPA 8 MeOH 1.32 83 I 0.47 120Sec-BuOH 25 / 89 I 0.13 122 Water 8 / I 1.3 Spray dried

TABLE 40 Solvents used during the polymorph screening experimentsSolvent ID MP ° C. BP ° C. Polarity (ε) Diethyl Ether DEE −116 35 4.34Dichloromethane DCM −97 40 9.08 Acetone ACT −94 56 20.7 Chloroform CHF−63 61 4.81 Methanol MET −98 65 33 n-Hexane NHX −95 69 2.02 EthylAcetate ETA −84 75 6.02 Ethanol ETH −114 78 24.3 1,2-Dimethoxy EthaneDMX −58 82 7.2 Water H20 0 100 78.54 Nitromethane NMT −29 101 35.91,4-Dioxane DIX 11 101 2.21 Acetonitrile ACN −48 82 36.6 p-Xylene PXY 13138 2.27 2-Methoxy Ethanol 2MX −85 124 — 1-Butanol 1BT −90 116 17.8 DMSODMS 17 189 47.2 DMF DMF −61 153 38.3 1-Propanol 1PR −127 97 20.1 EthylFormate EFM −80 54 7.1 t-Butyl Methyl Ether BME −109 55 — Methyl AcetateMAC −98 56.9 6.7 Tetrahydrofuran THF −108 65 7.52 Iso-Propyl Ether IPE−85 68 3.9 Methyl Ethyl Ketone MEK −87 80 18.5 Cyclohexane CHX 5 81 2.022-Propanol 2PR −90 82 18.3 Tert-Butanol TBT 24 83 12.5 Isopropyl AcetateIPA −73 89 — Propyl Acetate PAC −95 97 6.3 (±) 2-Butanol 2BT −115 9818.7 3-Pentanone 3PN −39 100 17.3 2-Methyl-1-Propanol MPR −108 108 —Toluene TOL −93 110 2.38 Diethyl Carbonate DEC −43 126 — Mesitylene MST−45 164 3.4 Benzonitrile BNT −13 188 26 Benzyl Alcohol ABZ −13 203 13Ethyl Benzoate EBZ −34 212 6

TABLE 41 Qualitative Solubility Solubility at Solubility at Room TempHigh Temp Solvent (RT) (HT) 1,2-Dimethoxy Ethane Low Low 1-Butanol High— 1-Propanol High — 2-Methoxy Ethanol High — Acetone Low LowAcetonitrile High — Chloroform High — Dichloromethane High — DiethylEther Low Low Dioxane Low High Dimethil sulfoxyde High — Ethanol High —Ethyl Acetate Low Low Methanol High — n-Hexane Low Low Nitromethane High— p-Xylene Low Low Water High — (±) 2-Butanol Low High1-Methyl-2-Pyrrolidone High — 1-Octanol Low Low 2-Methyl-1-Propanol High— 2-Propanol High — 3-Pentanone Low Low 4-Methyl-2-Pentanone Low LowBenzonitrile Low Low Benzyl Alcohol High — Cyclohexane Low Low DiethylCarbonate Low Low Dimethyl Formamide High — Ethyl Benzoate Low Low EthylFormate Low Low Isopropyl Acetate Low Low Iso-Propyl-Ether Low LowMesitylene Low Low Methyl Benzoate Low Low Methyl Ethyl Ketone Low LowMethyl-Cyclohexan Low Low n-Hexan Low Low Nitrobenezene Low Low PropylAcetate Low Low t-Butyl Methyl Ether Low Low Tert-Butanol Low LowTetrahydrofuran Low Low Toluene Low Low Low: a large amount of solidremains in suspension. Med: solid is not totally solved. High: clearsolution without solid suspended.

TABLE 42 Recrystallization Results Evaporation of Bupropion Hydrobromideat Room Temperature Solvent Recrystallization Result (Form) AcetonitrileForm I Acetone Form I Chloroform Form IV Dichloromethane Form I1,4-Dioxane Form I Ethyl Acetate Form I Ethanol Form I Water Form IMethanol Form I Nitromethane Form I p-Xylene Amorphous (±)2-Butanol FormII 2-Methyl-1-Propanol Form I 2-Propanol Form I 3-Pentanone Form II4-Methyl-2-Pentanone Form I Benzonitrile Form VII Diethyl Carbonate FormI Dimethyl Formamide Form I Ethyl Formate Form I Isopropyl Acetate FormI Mesitylene Amorphous Methyl Benzoate Form VII Methyl Ethyl Ketone FormI Propyl Acetate Form I Tert-Butanol Form I Tetrahydrofuran Form I

TABLE 43 Recrystallization Results Evaporation of Bupropion Hydrobromideat Low Temperature (4° C.) Solvent Recrystallization Result (Form)Acetonitrile Form I Acetone Form I Chloroform Form I DichloromethaneForm I 1,4-Dioxane Form I Ethyl Acetate Form I Ethanol Form I Water FormI Methanol Form I Nitromethane Form I p-Xylene Amorphous 2-Propanol FormI 3-Pentanone Form II Ethyl Formate Form I Isopropyl Acetate Form IMethyl Ethyl Ketone Form I Propyl Acetate Form I Tetrahydrofuran Form I

TABLE 44 Recrystallization Results Evaporation of Bupropion Hydrobromideat High Temperature (60° C.) Solvent Recrystallization Result (Form)1-Butanol Form I 1-Propanol Form I 2-Methoxy Ethanol Form I AcetonitrileForm I 1,4-Dioxane Form I DMSO Form I 1,2-Dimethoxy Ethane Form I WaterForm I Nitromethane Form I p-Xylene Amorphous Methyl Ethyl Ketone Form I2-Propanol Form I Tert-Butanol Form I Isopropyl Acetate Form I PropylAcetate Form I (±)2-Butanol Form I 3-Pentanone Form I2-Methyl-1-Propanol Form I Diethyl Carbonate Form I Dimethyl FormamideForm VII Benzonitrile Form VII Nitrobenzene Form I + VII Ethyl BenzoateForm VII

TABLE 45 Recrystallization Results Evaporation of Bupropion Hydrobromideat Low Pressure Solvent Recrystallization Result (Form) DichloromethaneForm I Ethyl Formate Form I 2-Methoxy Ethanol Form I Methyl Acetate FormI Chloroform Form I Methanol Form I Ethanol Form I Methyl Ethyl KetoneForm I 2-Propanol Form I Acetonitrile Form I Isopropyl Acetate Form I1-Propanol Form I Water Form I Ethyl Acetate Form I + VI 1,2-DimetoxyEthane Form I Tert-Butanol Form I Propyl Acetate Form I (±)2-ButanolForm I

TABLE 46 Form I Slurries Results - 7 days At Room Temperature SolventSlurry Result Ethyl acetate Form II n-Hexan Form II p-Xylene Form II1,2-Dimethoxy Ethane Form II Acetone Form II Diethyl ether Form II1,4-Dioxane Form V 1-Octanol Form II 3-Pentanone Form II4-Methyl-2-Pentanone Form II Benzonitrile Form II + VII Cyclohexane FormI Diethyl Carbonate Form II Ethyl Benzoate Form II Ethyl Formate Form IIIsopropyl Acetate Form II Iso-Propyl Ether Form II Mesitylene Form IIMethyl Benzoate Form II Methyl Ethyl Ketone Form II Methyl-CyclohexaneForm I Nitrobenzene Form II Propyl Acetate Form II t-Butyl Methyl EtherForm II Tert-Butanol Form II Tetrahydrofuran Form II Toluene Form II

TABLE 47 Form I Slurries Results - 30 days At Room Temperature SolventSlurry Result Ethyl acetate Form II n-Hexan Form II p-Xylene Form II1-Octanol Form II Acetone Form II t-Butyl Methyl Ether Form II TolueneForm II 4-Methyl-2-Pentanone Form II Methyl-Cyclohexane Form II MethylEthyl Ketone Form II Methyl Benzoate Form II Cyclohexane Form II EthylFormate Form II Isopropyl Acetate Form II Ethyl Acetate Form IIIso-Propyl Ether Form II Diethyl Carbonate Form II Diethyl Ether Form II1,2-Dimethoxy Ethane Form II 1,4-Dioxane Form V Tetrahydrofuran FormII + VII

TABLE 48 Form I + Form II Slurries Results - 7 days At Room TemperatureSolvent Slurry Result Ethyl acetate Form II n-Hexan Form II p-XyleneForm II 1,2-Dimethoxy Ethane Form II Acetone Form II Diethyl Ether FormII 1,4-Dioxane Form V

TABLE 49 Form II + Form III Slurries Results - 7 days At RoomTemperature Solvent Slurry Result Ethyl acetate Form II n-Hexan Form IIp-Xylene Form II 1,2-Dimethoxy Ethane Form II Acetone Form II DiethylEther Form II 1,4-Dioxane Form V

TABLE 50 Form II + Form IV Slurries Results - 7 days At Room TemperatureSolvent Slurry Result Ethyl acetate Form II n-Hexan Form II p-XyleneForm II 1,2-Dimethoxy Ethane Form II Acetone Form II Diethyl Ether FormII 1,4-Dioxane Form V

TABLE 51 Form II + Form V Slurries Results - 7 days At Room TemperatureSolvent Slurry Result Ethyl acetate Form II n-Hexan Form II p-XyleneForm II 1,2-Dimethoxy Ethane Form II Acetone Form II Diethyl Ether FormII 1,4-Dioxane Form V

TABLE 52 Form II + Form VI Slurries Results - 7 days At Room TemperatureSolvent Slurry Result Ethyl acetate Form II n-Hexan Form II p-XyleneForm II 1,2-Dimethoxy Ethane Form II Acetone Form II Diethyl Ether FormII 1,4-Dioxane Form V

TABLE 53 Form II + Form VII Slurries Results - 7 days At RoomTemperature Solvent Slurry Result Ethyl acetate Form II n-Hexan Form IIp-Xylene Form II 1,2-Dimethoxy Ethane Form II Acetone Form II DiethylEther Form II 1,4-Dioxane Form V

TABLE 54 Form I Precipitation Results By Anti-Solvent (Ethyl Acetate)addition at Room Temperature Solvent Precipitation ResultDichloromethane Form I 1-Butanol Form I 1-Propanol Form I 2-MethoxyEthanol Form I Dimethylformamide Form I Chloroform Form II Ethanol FormI Methanol Form I 1-Methyl-2-Pyrrolidone Form I 2-Methyl-1-Propanol FormI 2-Propanol Form I Benzyl Alcohol Form II

TABLE 55 Form I Precipitation Results By Oversaturated Solution at 100°C. Solvent Precipitation Result Water Form I Nitromethane Form Ip-Xylene Form I 1-Butanol Form I 1-Propanol Form VI 2-Methoxy EthanolForm I Dimethyl sulfoxyde Form I Dimethyl formamide Form I 1,4-DioxaneForm V 2-Methyl-1-Propanol Form I 1-Methyl-2-Pyrrolidone Form I(±)2-Butanol Form I

TABLE 56 Form I Characterization Peak List: Pos. [°2Th.] Height [cts]FWHM [°2Th.] d-spacing [Å] Rel. Int. [%] 6.6956 441.99 0.1171 13.201716.25 12.5142 1078.18 0.0669 7.07347 15.24 13.8338 495.49 0.0836 6.401577.01 14.1418 494.24 0.0836 6.26283 6.99 14.7981 708.72 0.1004 5.9865110.02 18.7980 129.44 0.1338 4.72073 1.83 19.6003 959.53 0.0836 4.5292813.57 21.2026 258.33 0.0669 4.19048 3.65 22.9330 604.92 0.1004 3.878068.55 23.6006 223.99 0.1171 3.76985 3.17 23.9869 597.98 0.1338 3.710008.45 24.3037 347.66 0.1004 3.66236 4.92 24.7629 271.46 0.2676 3.595473.84 25.5127 530.63 0.0669 3.49147 7.50 26.1117 7073.02 0.1338 3.41273100.00 26.8429 162.01 0.0502 3.32140 2.29 27.2174 261.03 0.0669 3.276543.69 27.5656 85.43 0.1004 3.23594 1.21 28.4838 255.21 0.1171 3.133683.61 28.9551 94.43 0.1338 3.08374 1.34 29.4381 462.52 0.0836 3.034236.54 30.6366 159.60 0.1338 2.91821 2.26 31.5518 511.29 0.0669 2.835627.23 32.3505 143.17 0.1004 2.76741 2.02 32.7014 2460.48 0.1020 2.7362534.79 32.7926 1562.72 0.0612 2.73564 22.09 33.8601 103.38 0.1224 2.645221.46 34.5527 153.32 0.1632 2.59377 2.17 35.5727 437.91 0.0612 2.521706.19 37.0456 106.77 0.2448 2.42475 1.51 37.8227 51.80 0.2856 2.376690.73 38.7631 92.78 0.1632 2.32117 1.31

TABLE 57 Form II Characterization Peak List: Pos. [°2Th.] Height [cts]FWHM [°2Th.] d-spacing [Å] Rel. Int. [%] 6.5301 1078.87 0.1171 13.5359254.01 12.1839 56.28 0.2007 7.26445 2.82 13.0302 341.23 0.3011 6.7944917.08 14.1804 144.73 0.1338 6.24587 7.24 15.9162 237.30 0.1171 5.5683811.88 16.5218 194.05 0.2007 5.36561 9.71 18.0133 104.98 0.2007 4.924575.26 18.8275 105.92 0.2007 4.71341 5.30 19.2806 106.21 0.2342 4.603655.32 20.6685 123.77 0.1004 4.29754 6.20 21.6359 140.14 0.1004 4.107527.01 21.9490 600.59 0.1171 4.04962 30.06 23.1059 1727.56 0.1506 3.8494386.48 24.1802 175.85 0.1338 3.68077 8.80 25.7472 1691.24 0.0612 3.4573484.66 25.8320 1997.69 0.0502 3.44904 100.00 26.8343 428.10 0.10043.32245 21.43 27.1433 175.53 0.1338 3.28532 8.79 27.8691 210.21 0.15063.20139 10.52 28.8111 507.17 0.1171 3.09883 25.39 29.6743 86.27 0.13383.01062 4.32 30.0692 343.86 0.0836 2.97197 17.21 31.8185 276.39 0.16732.81246 13.84 32.4172 421.65 0.0669 2.76188 21.11 33.2620 194.88 0.16732.69364 9.76 34.0877 90.26 0.2007 2.63025 4.52 34.8735 115.88 0.13382.57277 5.80 38.0294 133.57 0.1673 2.36621 6.69 38.7493 332.79 0.06692.32389 16.66 39.1289 148.12 0.1338 2.30222 7.41

TABLE 58 Form III Characterization Peak List: Pos. [°2Th.] Height [cts]FWHM [°2Th.] d-spacing [Å] Rel. Int. [%] 8.0596 279.60 0.0669 10.9701714.71 12.2853 367.57 0.1004 7.20473 19.34 12.8315 58.26 0.2007 6.899233.07 13.2434 71.14 0.1338 6.68559 3.74 15.2149 203.50 0.1171 5.8234410.71 15.6269 312.41 0.1004 5.67081 16.44 16.0036 698.13 0.1004 5.5381936.73 18.0692 1900.51 0.0836 4.90946 100.00 19.6718 224.36 0.08364.51297 11.81 20.6861 27.67 0.4015 4.29392 1.46 21.3980 87.79 0.20074.15264 4.62 22.7526 276.24 0.0502 3.90839 14.54 23.4234 433.75 0.33463.79796 22.82 24.2420 612.88 0.0669 3.67154 32.25 25.1221 1338.52 0.08363.54487 70.43 25.4298 765.07 0.0502 3.50267 40.26 26.5814 122.23 0.16733.35348 6.43 28.0071 89.35 0.2676 3.18593 4.70 28.9857 194.62 0.30113.08056 10.24 29.6568 289.74 0.1673 3.01236 15.25 30.6470 164.56 0.13382.91724 8.66 31.5990 64.65 0.2676 2.83150 3.40 32.3908 215.03 0.13382.76407 11.31 33.1938 318.21 0.0669 2.69901 16.74 34.0570 126.02 0.26762.63255 6.63 34.8593 60.37 0.2007 2.57379 3.18 36.3049 160.14 0.13382.47455 8.43 37.2156 100.45 0.2676 2.41606 5.29

TABLE 59 Form IV Characterization Peak List: Pos. [°2Th.] Height [cts]FWHM [°2Th.] d-spacing [Å] Rel. Int. [%] 4.2724 62.71 0.8029 20.6823010.43 10.7161 108.51 0.1673 8.25595 18.04 12.0264 176.45 0.2007 7.3592629.34 12.4816 210.22 0.1673 7.09184 34.95 14.1738 202.54 0.1673 6.2487533.68 14.8827 252.70 0.1338 5.95267 42.01 16.2511 79.85 0.2676 5.4544013.28 16.8644 150.41 0.2007 5.25738 25.01 17.1048 104.89 0.1004 5.1840417.44 17.8687 303.47 0.1673 4.96408 50.46 18.7619 119.28 0.2342 4.7297319.83 19.2392 97.51 0.2342 4.61345 16.21 20.0869 283.86 0.2342 4.4206347.19 21.7601 248.87 0.1673 4.08436 41.38 22.8957 601.46 0.1004 3.88428100.00 23.8771 324.04 0.1338 3.72681 53.88 24.4544 410.44 0.2342 3.6401368.24 25.5250 477.75 0.2007 3.48982 79.43 25.9015 275.99 0.1004 3.4399545.89 29.1312 52.91 0.4015 3.06550 8.80 30.5089 258.69 0.2007 2.9301443.01 32.0377 76.71 0.4684 2.79372 12.75 32.5333 42.72 0.2676 2.752287.10 33.0116 63.93 0.2342 2.71349 10.63 34.3203 34.09 0.5353 2.612965.67 35.9170 107.99 0.2007 2.50038 17.95 37.7676 59.12 0.2676 2.382019.83 38.5403 42.22 0.4015 2.33601 7.02

TABLE 60 Form V Characterization Peak List: Pos. [°2Th.] Height [cts]FWHM [°2Th.] d-spacing [Å] Rel. Int. [%] 7.4871 204.47 0.1004 11.8077428.74 11.8387 410.79 0.1338 7.47548 57.73 12.1526 209.30 0.1338 7.2831129.42 14.9302 611.31 0.2007 5.93382 85.92 15.1873 422.88 0.1171 5.8339559.43 17.3545 711.51 0.1171 5.10998 100.00 17.6294 576.40 0.1338 5.0309581.01 19.5302 48.43 0.2007 4.54538 6.81 20.8970 102.38 0.6022 4.2510714.39 22.4834 278.31 0.3346 3.95457 39.11 23.0890 609.75 0.1673 3.8522085.70 23.3165 586.83 0.1338 3.81512 82.48 23.9911 280.63 0.2676 3.7093639.44 24.9295 418.94 0.2676 3.57182 58.88 25.4770 303.12 0.2676 3.4962842.60 27.1047 244.42 0.1673 3.28991 34.35 27.2757 253.41 0.1004 3.2696835.62 28.8668 449.81 0.1171 3.09297 63.22 29.1165 459.78 0.1171 3.0670164.62 30.2032 224.45 0.3346 2.95910 31.55 31.2523 110.46 0.4015 2.8621115.52 32.1235 138.52 0.4015 2.78645 19.47 33.0720 178.41 0.3011 2.7086825.07 35.2183 65.08 0.2676 2.54837 9.15 35.7909 62.54 0.2676 2.508908.79 36.5174 66.19 0.2007 2.46064 9.30 37.1599 52.08 0.5353 2.41956 7.32

TABLE 61 Form VI Characterization Peak List: Pos. [°2Th.] Height [cts]FWHM [°2Th.] d-spacing [Å] Rel. Int. [%] 7.8496 1580.05 0.0836 11.2632467.30 11.8964 1854.21 0.0836 7.43939 78.98 12.6410 202.90 0.0836 7.002788.64 15.0380 777.82 0.0836 5.89152 33.13 15.2810 1173.32 0.0836 5.7984149.98 15.5243 1225.24 0.0836 5.70807 52.19 16.1145 164.99 0.0669 5.500307.03 17.6095 2347.80 0.1004 5.03657 100.00 19.0798 169.45 0.1004 4.651657.22 19.3067 302.45 0.0836 4.59748 12.88 20.3324 103.42 0.1171 4.367824.40 21.1331 526.05 0.1004 4.20409 22.41 22.4375 700.44 0.1004 3.9625729.83 22.9995 1347.34 0.1004 3.86699 57.39 23.3043 684.79 0.1004 3.8171029.17 23.7841 1744.10 0.1171 3.74117 74.29 24.5054 230.40 0.1004 3.632669.81 24.7579 434.11 0.1004 3.59618 18.49 25.0253 1655.56 0.1171 3.5583670.52 25.5033 344.02 0.1171 3.49274 14.65 26.0438 327.56 0.0669 3.4214713.95 26.2753 170.54 0.1004 3.39185 7.26 26.6025 80.83 0.1338 3.350863.44 27.5096 292.81 0.1004 3.24241 12.47 28.1175 878.41 0.1171 3.1736737.41 28.7048 251.20 0.0836 3.11006 10.70 29.0435 1318.15 0.1004 3.0745656.14 29.4202 234.78 0.0836 3.03604 10.00 30.3099 340.86 0.0836 2.9489214.52 30.9237 358.99 0.1338 2.89177 15.29 31.6783 193.78 0.1338 2.824598.25 32.0151 172.84 0.1338 2.79564 7.36 32.4820 165.13 0.1338 2.756517.03 32.8446 219.60 0.1673 2.72691 9.35 33.2526 169.79 0.1506 2.694377.23 33.7436 333.64 0.0669 2.65628 14.21 35.1498 145.85 0.1004 2.553176.21 35.4257 223.46 0.2342 2.53392 9.52 36.1195 160.13 0.1171 2.486826.82 36.6412 148.76 0.1004 2.45261 6.34 37.3742 134.83 0.1004 2.406175.74 38.9668 127.14 0.1004 2.31142 5.42

TABLE 62 Form VII Characterization Peak List: Pos. [°2Th.] Height [cts]FWHM [°2Th.] d-spacing [Å] Rel. Int. [%] 9.8602 13202.67 0.0787 8.9705864.80 13.8310 1102.79 0.0590 6.40286 5.41 18.6304 430.48 0.0590 4.762832.11 19.4724 20373.14 0.0590 4.55874 100.00 19.5919 19333.60 0.05904.53120 94.90 19.9962 629.82 0.0787 4.44048 3.09 20.2520 337.93 0.05904.38498 1.66 21.8775 1392.67 0.0590 4.06271 6.84 23.3213 545.78 0.07873.81436 2.68 24.0376 1305.06 0.0787 3.70229 6.41 25.9551 143.45 0.09843.43296 0.70 27.6781 626.31 0.0787 3.22304 3.07 28.1796 573.45 0.07873.16682 2.81 29.3112 8508.46 0.0720 3.04456 41.76 29.4207 10351.490.0394 3.03599 50.81 31.0133 836.93 0.0984 2.88362 4.11 32.6067 111.060.0984 2.74626 0.55 35.5593 84.45 0.1968 2.52471 0.41 36.8168 190.510.1771 2.44131 0.94 39.5031 2222.25 0.0590 2.28127 10.91

TABLE 63 Amorphouse Form Characterization Peak List: Pos. [°2Th.] Height[cts] FWHM [°2Th.] d-spacing [Å] Rel. Int. [%] 14.2290 373.13 0.76736.21949 100.00 14.2645 186.57 0.7673 6.21949 50.00 17.1264 157.26 0.39145.17326 42.15 17.1692 78.63 0.3914 5.17326 21.07 18.7217 154.19 0.47894.73588 41.32 18.7686 77.09 0.4789 4.73588 20.66 21.8014 177.84 1.46984.07334 47.66 21.8563 88.92 1.4698 4.07334 23.83

TABLE 64 TGA - DSC Summary Polymorph DSC (onset ° C.) TGA (mass change)Form I 236.81 −100.04%  Form II 194.20 — 236.65 −93.35% Form III 77.66 −6.06% 236.97 −85.54% Form IV 149.89  −9.41% 233.14   83.89% Form V — −4.58% 237.85  −90.5% Form VI 235 −97.68% Form VII —  −6.58% — −17.52%268.7 −71.65%

1. Bupropion hydrobromide in crystalline form, characterized by at leastone of the following properties: PXRD as in FIG. 31, DSC as in FIG. 32,TGA as in FIG. 33, IR as in FIG.
 34. 2. Bupropion hydrobromide incrystalline form, characterized by at least one of the followingproperties: PXRD as in FIG. 35, DSC as in FIG. 36, TGA as in FIG. 37, IRas in FIG.
 38. 3. Bupropion hydrobromide in crystalline form,characterized by at least one of the following properties: PXRD as inFIG. 39, DSC as in FIG. 40, TGA as in FIG. 41, IR as in FIG.
 42. 4.Bupropion hydrobromide in crystalline form, characterized by at leastone of the following properties: PXRD as in FIG. 43, DSC as in FIG. 44,TGA as in FIG. 45, IR as in FIG.
 46. 5. Bupropion hydrobromide inamorphous form, characterized by PXRD as in FIG.
 47. 6. Bupropionhydrobromide in amorphous form, characterized by PXRD as in FIG.
 48. 7.A composition comprising the bupropion hydrobromide according to claim1, 2, 3, 4, 5 or 6 and a pharmaceutically acceptable carrier orexcipient.
 8. The composition according to claim 7, further comprisingat least one other drug other than bupropion hydrobromide selected fromthe group consisting of anti-depressants, anti-anxiety agents, steroidalinflammatories, non-steroidal inflammatories, SSRIs, anti-migraineagents, anti-emetics, drugs for treating abuse, appetite modulators,anti-virals, vasodilators, anti-pain agents, and combinations thereof.9. The composition according to claim 7 further comprising at least oneother drug other than bupropion hydrobromide selected from the groupconsisting of a monoamine oxidase (MAO) inhibitor, a tricyclicantidepressant, a serotonin reuptake inhibitor, a selectivenorepinephrine reuptake inhibitor (SNRIs), aminoketones, serotoninantagonists, dopamine reuptake inhibitors, dual reuptake inhibitors,norepinephrine enhancers, serotonin activity enhancers, dopamineactivity enhancers, and combinations thereof.
 10. The composition ofclaim 7, in the form of a microparticle comprising a solid core, saidcore comprising the bupropion hydrobromide and the at least onepharmaceutically acceptable excipient, said core of said microparticlebeing at least partially surrounded by a controlled release coat whichpermits entry of an aqueous liquid into the core and delivery of thebupropion hydrobromide from the core to the exterior of themicroparticle through the controlled release coat.
 11. The compositionof claim 7, in the form of a tablet comprising a core comprising thebupropion hydrobromide and a controlled release coating at leastpartially surrounding said core, the coating comprising at least onewater-soluble polymer, at least one water-insoluble polymer, andoptionally a plasticizer.
 12. A method of treating depression, seasonaleffective disorder, obesity, anxiety, obsessive compulsive disorder,post traumatic stress disorder (PTSD), panic disorder, disordersrequiring a stimulant effect, attention deficit/hyperactiviy disorder(ADHD), narcolepsy, hypersomnia, female sexual dysfunction, male sexualdysfunction, premenstrual syndrome, premenstrual dysphoric disorder,neuropathic pain, fibromyalgia, diabetic neuropathy, viral infection,sleep apnea, sleep disorders or migraines comprising administering aneffective amount of the bupropion hydrobromide of claim 1, 2, 3, 4, 5 or6 to treat depression, seasonal effective disorder, obesity, anxiety,obsessive compulsive disorder, post traumatic stress disorder (PTSD),panic disorder, disorders requiring a stimulant effect, attentiondeficit/hyperactiviy disorder (ADHD), narcolepsy, hypersomnia, femalesexual dysfunction, male sexual dysfunction, premenstrual syndrome,premenstrual dysphoric disorder, neuropathic pain, fibromyalgia,diabetic neuropathy, viral infection, sleep apnea, sleep disorders ormigraines to a subject in need thereof.
 13. A composition comprising twoor more of the following forms of bupropion hydrobromide:(a) acrystalline form having the following properties PXRD as in FIG. 31, DSCas in FIG. 32, TGA as in FIG. 33, IR as in FIG. 34; (b) a crystallineform having the following properties PXRD as in FIG. 35, DSC as in FIG.36, TGA as in FIG. 37, IR as in FIG. 38; (c) a crystalline form havingthe following properties PXRD as in FIG. 39, DSC as in FIG. 40, TGA asin FIG. 41, IR as in FIG. 42; (d) a crystalline form having thefollowing properties PXRD as in FIG. 43, DSC as in FIG. 44, TGA as inFIG. 45, IR as in FIG. 46; (e) an amorphous form having the followingproperty PXRD as in FIG. 47; and (f) an amorphous form having thefollowing property PXRD as in FIG. 48.